CN103037852B - The peroral dosage form of bendamustine and therapeutical uses thereof - Google Patents

The peroral dosage form of bendamustine and therapeutical uses thereof Download PDF

Info

Publication number
CN103037852B
CN103037852B CN201180038034.4A CN201180038034A CN103037852B CN 103037852 B CN103037852 B CN 103037852B CN 201180038034 A CN201180038034 A CN 201180038034A CN 103037852 B CN103037852 B CN 103037852B
Authority
CN
China
Prior art keywords
day
bendamustine
tablet
composition
dosage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201180038034.4A
Other languages
Chinese (zh)
Other versions
CN103037852A (en
Inventor
乌尔里希·帕察克
陶菲克·奥瓦塔斯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Deutschland GmbH
Original Assignee
Astellas Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44261747&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN103037852(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Astellas Deutschland GmbH filed Critical Astellas Deutschland GmbH
Publication of CN103037852A publication Critical patent/CN103037852A/en
Application granted granted Critical
Publication of CN103037852B publication Critical patent/CN103037852B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention provides a kind of pharmaceutical composition of oral administration, said composition comprises: as bendamustine or its pharmaceutically useful ester of active component, salt or solvate, with pharmaceutically acceptable excipient, and when the oar formula device that is 50rpm according to European Pharmacopoeia use rotating speed is at 500ml, pH value is while measuring in 1.5 dissolution medium, described pharmaceutical composition demonstrates such bendamustine stripping behavior: stripping at least 60% after 20 minutes, stripping at least 70% after 40 minutes, and stripping at least 80% after 60 minutes, and wherein said pharmaceutically acceptable excipient is for selecting free GREMAPHOR GS32 or derivatives thereof, and pharmaceutically acceptable non-ionic surface active agent in the group of the block copolymer of oxirane and expoxy propane composition, or for selecting free monose, disaccharides, compound sugar, cyclic oligosaccharide, pharmaceutically useful sugar in the group of one or more compositions in polysaccharide and sugar alcohol, the weight ratio of wherein said active component and described sugared excipient is at 1:(1-5) scope in. the invention still further relates to the aforementioned pharmaceutical compositions for the treatment of the purposes of following medical science symptom for per os, described medical science symptom is selected from chronic lymphocytic leukemia, ALL, chronic myelocytic leukemia, acute myeloblastic leukemia, Hodgkin's disease, NHL, Huppert's disease, breast cancer, oophoroma, ED-SCLC and non-small cell lung cancer. the invention still further relates to the aforementioned pharmaceutical compositions for such use, wherein dosage regimen at least comprises: the 1st day and the 2nd day application dosage are 100mg/m2/ people is to 600mg/m2/ people's bendamustine, optionally, uses intravenous injection in the 1st day to the 5th day or oral dose is 50mg/m2To 150mg/m2Corticosteroid, and optionally use the other activating agent of suitable dosage, this activating agent selects the group of free CD20 specific antibody, anthracycline derivative, vinblastine or platinum derivatives composition; And after interval 2-4 week, described dosage regimen is repeated 4 to 15 times.

Description

The peroral dosage form of bendamustine and therapeutical uses thereof
Technical field
The present invention relates to the peroral dosage form that comprises bendamustine or its pharmaceutically useful ester, salt or solvate, and controlTreat purposes.
Background technology
Bendamustine (4-[5-[bis-(2-chloroethyl) amino]-1-tolimidazole-2 base] butyric acid, it is a kind of nitrogenMustard) be a kind of alkylating agent with difunctional alkylation activity. It is corresponding to following structural formula (I):
It seems that bendamustine can other alkylating agent not produced to any cross resistance, and this was to accepting alkanisationThe patient of agent treatment carries out chemotherapy aspect and has advantage.
Bendamustine is synthetic in German Democratic Republic (GDR) at first. At 1971 to 1992 with trade nameIn the commercial product of selling, bendamustine hydrochloride is active component. From that time, bendamustine hydrochlorideIn Germany with trade nameSell, and be widely used in treatment chronic lymphocytic leukemia, non-Hodgkin's pouringBar knurl and Huppert's disease.
Commercially available product comprises bendamustine hydrochloride freeze-dried powder, and this freeze-dried powder redissolves with water for injection and produces concentratedThing. Diluted with 0.9% sodium-chloride water solution afterwards, thereby obtained the final solution that infusion is used. Final solution is by approximatelyIn the time of 30 minutes to 60 minutes, carry out venoclysis and be administered to patient.
The hydrolysis of two-2-chloroethyl amino group of bendamustine in water can cause drug effect to reduce and form impurity(B.Maas etc. (1994), Pharmazie49:775-777). Therefore after freeze-dried powder redissolves, must use immediately and (conventionally existHospital or at least under medical control, carry out). In addition, be reported that redissolution process is difficult. This process may need to be greater than30 minutes. In addition, concerning the medical professional who is responsible for product to redissolve, redissolving with the process of 2 steps is loaded down with trivial details and expenseTime.
Preiss etc. (1985) (Pharmazie40:782-784) have compared 7 patients respectively with 4.2mg/kg extremelyThe dosage of 5.5mg/kg after intravenous and oral administration, the pharmacokinetics of bendamustine hydrochloride in its blood plasma. By citySell productVenoclysis liquid administration in 3 minutes of preparation, the oral drugs of DE are to compriseThe capsule form of 25mg bendamustine hydrochloride is taken. The capsule quantity that patient takes be 10 to 14 not etc., 250mg is extremelyThe absolute oral dose of 350mg. After oral administration, maximum blood plasma level can be detected within an hour. As calculated, averageOral administration biaavailability is 57%, and scope is 25% to 94%, and this demonstrates large interindividual variation (%CV=44%). Preiss etc. existIn document (Z.Klin.Med.44 (1989): 125-129) afterwards, report larger interindividual variation (25% to 121%)The similar research of carrying out.
Weber(1991) (Pharmazie46 (8): 589-591) studied bendamustine hydrochloride B6D2F1-mouseIn bioavilability, and find that medicine obtains not exclusively from gastrointestinal absorption, this makes bioavilability only for approximately 40%.
Patent documentation US2006/0128777A1 has recorded the method for the treatment of cancer, and the feature of the method is to resist generallyDead cell and the composition that contains bendamustine. In these compositions, there are capsule, tablet, pill, powder or granulatedThe peroral dosage form of formula, wherein, reactive compound can be for example, with at least one inert excipient (sucrose, lactose or starch) mixedClose. But it does not illustrate concrete composition.
It is in 2.0 water that bendamustine hydrochloride is only marginally dissolved in pH value, and trace or denier ground are dissolved in one and areRow organic solvent. But, observe it and in ethanol and methyl alcohol, demonstrated good dissolubility. Therefore, no wonderThat, as studied with Weber in Preiss etc., oral bendamustine composition can produce relatively poor biological utilisationDegree result and large interindividual variation.
Once consider the problem of commercially available intravenous formulation water redissolution meeting existence and stability aspect, and in order to improvePatient compliance, people need a kind of stabilizer type that contains bendamustine always for a long time, and this formulation is easy to patientUse, and good bioavilability is provided and do not have between large individuality and individual in difference. People also need a kind of medicineComposition, it makes bendamustine can be absorbed completely or be absorbed at least to a great extent under one's belt, therebyAvoid or reduce bendamustine and degrade in small intestine or large intestine.
Summary of the invention
In order to address the above problem, the inventor is studied in detail. They have finally successfully obtained thisThe stable pharmaceutical composition of invention. These compositions are suitable for oral administration, and comprise: as the bendamustine of active componentSpit of fland or its pharmaceutically useful ester, salt or solvate, and at least one pharmaceutically acceptable excipient, described composition is good except havingStability beyond, also in acid medium, having good stripping behavior, good bioavilability and treatment can acceptIndividuality between and individual in difference.
Brief description of the drawings
Fig. 1 illustrates with the form of prior art capsule (reference example 1) with the liquid filled hard capsules preparation of embodiment 2After form is used bendamustine hydrochloride to doggie, the mean plasma concentration of gained is with respect to the curve of time. Fig. 1 obviously showsGo out, with prior art with reference to compared with capsule preparations, this liquid filled hard capsules preparation provides higher bendamustineLarge concentration.
Fig. 2 illustrate with intravenous formulation (Germany withSell) form and with the liquid of embodiment 2After the form of body filled hard capsule preparation is used bendamustine hydrochloride to cancer patient, the mean plasma concentration of gained is relativeIn the curve of time.
Fig. 3 shows doggie is used with prior art capsule form and embodiment 15 to 17(tablets 1 to 3) and embodiment18(preparation 3) (tablet is relative for the mean plasma concentration that obtains after the bendamustine hydrochloride of tablet formulation form of (tablet 4)In capsule) with respect to the curve of time. Fig. 3 obviously illustrates, compared with the capsule of prior art, it is higher that tablet formulation can provideBendamustine Cmax.
Fig. 4 illustrates the flow chart of wet granulation preparation test.
Detailed description of the invention
The present invention relates to a kind of pharmaceutical composition of oral administration, this pharmaceutical composition comprises: as the benzene of active componentBendamustine or its pharmaceutically useful ester, salt or solvate, and pharmaceutically acceptable excipient, and when using rotating speed according to European PharmacopoeiaWhen measuring in the oar formula device of the 50rpm dissolution medium that is 1.5 in 500ml, pH value, described pharmaceutical composition demonstrates like thisBendamustine stripping behavior: stripping stripping at least 70% after at least 60%, 40 minutes after 20 minutes, and molten after 60 minutesGo out at least 80%, and wherein said pharmaceutically acceptable excipient is for selecting free GREMAPHOR GS32 or derivatives thereof and epoxyPharmaceutically acceptable non-ionic surface active agent in the group of the block copolymer composition of ethane and expoxy propane, or be freely list of choosingPharmaceutically useful sugar in the group of one or more compositions in sugar, disaccharides, compound sugar, cyclic oligosaccharide, polysaccharide and sugar alcohol, itsDescribed in the weight ratio of active component and described sugared excipient at 1:(1-5) scope in.
In the first embodiment of the present invention, the present invention relates to a kind of pharmaceutical composition of oral administration, said compositionComprise: as bendamustine or its pharmaceutically useful ester, salt or the solvate of active component, and pharmaceutically acceptable excipient, shouldPharmaceutically acceptable excipient is to select the block of free GREMAPHOR GS32 or derivatives thereof and oxirane and expoxy propane to be total toNon-ionic surface active agent in the group of polymers composition.
An embodiment of the first embodiment of the present invention is pharmaceutical composition, and it comprises: bendamustine or itsPharmaceutically useful ester, salt or solvate, and pharmaceutically acceptable excipient, this pharmaceutically acceptable excipient is for selecting free polyethoxylated castor-oil plantNon-ionic surface active agent in the group of the block copolymer composition of oil or derivatives thereof and oxirane and expoxy propane,Wherein, described composition is adapted to pass through and packs in snap fit capsule and oral administration.
Another embodiment of the first embodiment of the present invention is form (snap fit capsule) warp with solid dosage formsThe pharmaceutical composition used of mouth, said composition comprises: as the bendamustine of active component or its pharmaceutically useful ester, salt or moltenAgent compound, and pharmaceutically acceptable excipient, this pharmaceutically acceptable excipient selects free GREMAPHOR GS32 or derivatives thereof, Yi JihuanThe group of the block copolymer composition of oxidative ethane and expoxy propane, and be preferably selected from by Cremophor RH40(macrogolglycerolhydroxystearate), polyoxyethylene-35-castor oil (polyoxyl-35-castorOil) and ethylene oxide/propylene oxide block copolymer (L44NF or124) group of composition, itsIn, the use of described specific non-ionic surface active agent has produced such stripping behavior: through using and turn according to European PharmacopoeiaSpeed is for measuring in the oar formula device of the 50rpm dissolution medium that is 1.5 in 500ml, pH value, and bendamustine is molten after 20 minutesGo out stripping at least 70% after at least 60%, 40 minutes, and stripping at least 80% after 60 minutes, and preferably, it has produced like thisStripping behavior: bendamustine stripping stripping at least 70% after at least 60%, 20 minutes after 10 minutes, and molten after 30 minutesGo out at least 80%.
A preferred embodiment of described the first embodiment is with solid dosage forms (snap fit capsule) oral administrationPharmaceutical composition, said composition comprises bendamustine hydrochloride and as the poly-second of the hydroxy stearic acid of pharmaceutically acceptable excipientGlycol glyceride, wherein, the use of described specific non-ionic surface active agent has produced such stripping behavior: through according to EuropeIn the dissolution medium that the oar formula device that continent pharmacopeia use rotating speed is 50rpm is 1.5 in 500ml, pH value, measure, bendamustine existsStripping stripping at least 70% after at least 60%, 20 minutes after 10 minutes, and stripping at least 80% after 30 minutes.
In the second embodiment of the present invention, the present invention relates to a kind of pharmaceutical composition, it comprises: as active componentBendamustine or its pharmaceutically useful ester, salt or solvate, and at least one is selected from monose, disaccharides, compound sugar, ring-typeThe pharmaceutically acceptable excipient of compound sugar, many Saccharide and saccharide alcohols. Preferably, the weight ratio between described active component and described excipient existsIn the scope of 1:1 to 1:5, preferably, in the scope of 1:2 to 1:5, be more preferably selected from the ratio of 1:5 and 1:2.
In an embodiment of the second embodiment of the present invention, the present invention relates to a kind of solid formulation of oral administrationType pharmaceutical composition, said composition comprises: as bendamustine or its pharmaceutically useful ester, salt or the solvation of active componentThing, and at least one pharmaceutically acceptable excipient, this pharmaceutically acceptable excipient is for selecting free monose, disaccharides, compound sugar, cyclic oligomerPharmaceutically useful sugar in the group of one or more compositions in sugar, polysaccharide and sugar alcohol, wherein, described active component and described taxThe weight ratio of shape agent is in the scope of 1:1.
In the further embodiment of the second embodiment of the present invention, the present invention relates to one and be suitable for oral administrationPharmaceutical composition as solid dosage form, said composition comprises: as the bendamustine of active component or its pharmaceutically useful ester, salt orSolvate, and at least one pharmaceutically acceptable excipient, this pharmaceutically acceptable excipient is for selecting free monose, disaccharides, compound sugar, ring-typePharmaceutically useful sugar in the group of one or more compositions in compound sugar, polysaccharide and sugar alcohol, wherein, described active component and instituteState the weight ratio of sugared excipient in the scope of 1:2 to 1:5, and said composition demonstrates following bendamustine stripping rowFor: in the dissolution medium that is 1.5 in 500ml, pH value through the oar formula device that is 50rpm according to European Pharmacopoeia use rotating speed, measure,Bendamustine is stripping at least 70% in stripping at least 60%, 40 minutes in 20 minutes, and stripping at least 80% in 60 minutes.
In the scope of above-mentioned the second embodiment, further preferred embodiment is such pharmaceutical composition, itsDescribed in pharmaceutically useful sugar select the group of one or more compositions in free monose, disaccharides and compound sugar, wherein, described active becomeDivide with the weight ratio of described sugared excipient in the scope of 1:2 to 1:5, and said composition demonstrates following bendamustineStripping behavior: in the dissolution medium that is 1.5 in 500ml, pH value through the oar formula device that is 50rpm according to European Pharmacopoeia use rotating speedMeasure, bendamustine is stripping at least 70% in stripping at least 60%, 40 minutes in 20 minutes, and in 60 minutes stripping is at least80%。
The present invention is based on so unexpected discovery: by by some non-ionic surface active agent or some sugar or sugaredAlcohol is introduced in pharmaceutical composition can obtain the stable bendamustine composition with specific and good stripping behavior. ?Through finding, if by following pharmaceutically acceptable non-ionic surface active agent as comprising bendamustine or its pharmaceutically useful ester, saltOr solvate is as the excipient in the pharmaceutical composition of active component, described composition is at stability and catabolite, moltenThe bioavilability difference aspect of artificial situation, bioavilability and reduction obtains good especially behavior, wherein said can medicineSelect the embedding of free GREMAPHOR GS32 or derivatives thereof and oxirane and expoxy propane with non-ionic surface active agentThe group of section copolymer composition, and be preferably selected from by Cremophor RH40, polyoxyethylene-35-castor oil andEthylene oxide/propylene oxide block copolymer (L44NF or124) group of composition. Containing benzeneIn the composition of bendamustine, introduce above-mentioned non-ionic surface active agent and produced such stripping behavior: through according to European medicineIn the dissolution medium that the oar formula device that allusion quotation use rotating speed is 50rpm is 1.5 in 500ml, pH value, measure, bendamustine is at 20 pointsStripping stripping at least 70% after at least 60%, 40 minutes after clock, and stripping at least 80% after 60 minutes, and it has preferably producedSuch stripping behavior: bendamustine stripping stripping at least 70% after at least 60%, 20 minutes after 10 minutes, and 30 minutesRear stripping at least 80%.
Further find, if will following pharmaceutically useful sugar be used as comprise bendamustine or its pharmaceutically useful ester,Salt or solvate be as the excipient in the pharmaceutical composition of active component, described composition stability, compressing tablet performance,Stripping property and these aspects of impurity formative can reach good especially behavior, wherein said pharmaceutically useful sugar select free monose,The group of one or more compositions in disaccharides, compound sugar, cyclic oligosaccharide, many Saccharide and saccharide alcohols, and be preferably select free monose,The group of one or more compositions in disaccharides and compound sugar. Above-mentioned carbohydrate makes described compositions display go out following bendamustineStripping behavior: in the dissolution medium that is 1.5 in 500ml, pH value through the oar formula device that is 50rpm according to European Pharmacopoeia use rotating speedMeasure, bendamustine is stripping at least 70% in stripping at least 60%, 40 minutes in 20 minutes, and in 60 minutes stripping is at least80%。
In the above-mentioned scope of the second embodiment of the present invention, can use monose, disaccharides, compound sugar, cyclic oligomerAny combination of one or more in sugared, many Saccharide and saccharide alcohols.
Especially have been found that specific sugar and the pharmaceutical composition good especially row aspect stability and stripping propertyFor relevant. Sugar in the composition of the second embodiment of the present invention is preferably anhydrous dextrose, Dextrose monohydrous, lactose monohydrateAlcohol, trehalose, D-sorbite, antierythrite, a water maltose, sweet mellow wine, Lactis Anhydrous, lactose monohydrate, maltitol, wood sugarAlcohol, sucrose, sucrose 97%+ maltodextrin 3%, beta-schardinger dextrin-, D-five water gossyposes, D-melezitose monohydrate and microcrystalline celluloseElement. Pharmaceutical composition of the present invention demonstrates good tabletting characteristics, Fast Stripping behavior and medicinal suitable stability.
Above-mentioned sugar forms the preferred embodiment of second embodiment of the invention, and can use its any combination. ExcellentSelection of land, the ratio of described active component and above-mentioned sugar in the scope of 1:1 to 1:5, preferably in the scope of 1:2 to 1:5, andMore preferably be selected from the ratio of 1:5 and 1:2.
The further preferred embodiment of second embodiment of the invention is a kind of solid dosage medicine of oral administrationComposition, said composition comprises: as bendamustine or its pharmaceutically useful ester, salt or the solvate of active component, and extremelyFew one is selected from anhydrous dextrose, Dextrose monohydrous, lactose monohydrate alcohol, trehalose, D-sorbite, antierythrite, a water Fructus Hordei GerminatusSugar, sweet mellow wine, Lactis Anhydrous, lactose monohydrate, maltitol, xylitol, sucrose, sucrose 97%+ maltodextrin 3%, beta-schardinger dextrin-,The pharmaceutically acceptable excipient of D-five water gossyposes, D-melezitose monohydrate and microcrystalline cellulose, described compositions display goes out: benzene reachesMo Siting is stripping at least 70% in stripping at least 60%, 20 minutes in 10 minutes, and stripping at least 80% in 30 minutes.
Particularly preferred sugar is sweet mellow wine, maltitol, antierythrite, xylitol, lactose, sucrose, glucose(glucose), D-sorbite, maltose, trehalose, lactitol and dextrose (dextrose) (anhydrous or monohydrate), andAnd the weight ratio of described active component and described sugar is preferably in the scope of 1:2 to 1:5. The present invention also comprises the scope of above-mentioned sugarThe combination of two or more interior sugar.
Those skilled in the art can select suitable combination completely in the above-mentioned sugared excipient of mentioning, and obtainMust demonstrate the composition of following bendamustine stripping behavior: through use the oar formula dress that rotating speed is 50rpm according to European PharmacopoeiaIn the dissolution medium that to put in 500ml, pH value be 1.5, measure, bendamustine is in 20 minutes in stripping at least 60%, 40 minutesStripping at least 70%, and stripping at least 80% in 60 minutes.
In preferred embodiments, described composition is the form of tablet, granule or pill.
Preferred formulation is tablet, and is preferably quick-release tablet (immediatereleasetablet), fast-release tabletAgent refers to after tablet is placed in aqueous medium (being preferably acid medium), this tablet release of active ingredients very fast.Term tablet also comprises quickly disintegrating tablet, wherein has dispersing tablet and effervescent tablet.
The most frequently used method for preparing tablet thereof is direct tablet compressing, non-slurry pelletizing and wet granulation. Direct tablet compressing relates at compressing tabletOn machine by the mixture compression forming that contains active component and excipient (L.Lachman etc., TheTheoryandPracticeofIndustrialPharmacy, the third edition, 1986). The activity in order to prepare with homogeneous content becomesThe tablet dividing, the mixture of moulding to be compressed must not only have good mobility but also have good compressible mouldability. AndNon-always can for example, by adding suitable excipient (lubricant, antiadhesives and flow improver additive) to obtain in mixtureObtain mobility well. Therefore before compression forming, usually described mixture is carried out to granulation.
Granulation is to make powder mixture form the process of the aggregation (being called particle) of approximate spherical or regular shape. ShouldProcess can realize by non-slurry pelletizing method and wet granulation method. Granulation is also for having the mixture of powders of low cohesive forceTransform into aggregation, when by this aggregation compression forming, obtain having the tablet of good cohesion matter.
In the situation of quickly disintegrating tablet, advantageously tool of active component (its optionally with one or more mixed with excipients)There is dressing, to cover the taste of described active component, and/or protect described active component not to be subject to by illumination and/or moistureCaused possible adverse effect, and in the situation of bendamustine, in order to protect mucous membrane of mouth not to be subject to by activateThe adverse effect that compound causes. For this purpose, preferably carry out preparation and fabrication particle according to following further instruction.
Expression way " particle " refers to the aggregation of particle, sometimes also referred to as pellet. Particle is conventionally by compacting and/or pressurePrepared by contracting forming technique (non-slurry pelletizing); Or adopt the liquid that is wherein optionally dissolved with wet granulation adhesive, by wet(PharmaceuticalSciences of Remington, the 18th edition, nineteen ninety, the 1641st page) prepared in method granulation. Wet methodGranulating technique also comprises extruding technology. Therefore term particle also comprises piller, bead and extrudate, and wherein, particle is example preferablySon is piller.
Piller can be described as to have certain density and diameter is about 1.0 to 1.6mm granule, it is by rightPowder mixture is used and is extruded that round as a ball pharmaceutical technology is prepared from.
Active component (its optionally with one or more mixed with excipients) can advantageously have dressing, to cover described workThe taste of property composition, and/or protect described active component not to be subject to by illumination and/or the caused possible harmful shadow of moistureRing, and/or protection mucous membrane of mouth is not subject to the adverse effect being caused by active component.
Pill is solid dosage forms little and circle, by active component being added soft triglyceride mixture prepare.By described mixture rolling growth line, the also rolling that afterwards this long line is cut into pieces (J.T.Carstensen,Pharmaceuticalprinciplesofsoliddosageforms, 1993, TechnomicPublishingCompany, the 63rd page).
Formulation of the present invention is preferably prepared by dry method compact technique. Suitable technology is for example Remington'sPharmaceuticalSciences,, nineteen ninety, describes in the 1644th page to some extent by the 18th edition. They comprise non-slurry pelletizing, rollPress and direct pressing. In the time using these technology to prepare tablet, adopt straight pressing more favourable.
Preferably there is dressing according to formulation of the present invention. Dressing has different objects: can be used for covering in compositionThe taste of active component used protects described active component not to be subject to by illumination and/or caused possible the having of moisture simultaneouslyEvil impact, for example, be oxidized, degraded etc. In addition, coatings can prevent that patient's mucous membrane of mouth from suffering to be caused by active componentDestruction.
Can for example, by technology well known in the art (spraying and microencapsulation) coatings be applied to described doseType. Concerning tablet, it can be the form of film coating, sugar-coat or pressed coated. Preferably adopt film coating procedure(PharmaceuticalSciences of Remington, the 18th edition, nineteen ninety, the 1666th page). According to active componentNeed and quickly disintegrating tablet carried out in the situation of dressing, indivedual particles may be suitable for wrapping before compression forming is tabletClothing.
Expression way " its pharmaceutically useful ester " refers to any pharmaceutically useful ester of bendamustine, for example bendamustine withThe ester that alkylol forms and the ester forming with sugar alcohol. The example of alkylol is C1-6Alkylol, for example methyl alcohol, ethanol, propyl alcohol, differentPropyl alcohol, butanols and the tert-butyl alcohol. The example of sugar alcohol be sweet mellow wine, maltitol, sorbierite, antierythrite, ethylene glycol, glycerine, AhSugar alcohol, xylitol and lactitol. The preferred example of bendamustine ester is ethyl ester, isopropyl ester, Nitranitol and sorbitol ester,Be preferably bendamustine ethyl ester.
Expression way " its pharmaceutically useful salt " refers to and is applied to patient's (directly or indirectly) so that appointing of bendamustine to be providedThe salt of what pharmaceutically useful bendamustine. This term also comprises the officinal salt of bendamustine ester. But should think can notMedicinal salt is also included within scope of the present invention, because these compounds can be for the preparation of pharmaceutically useful salt. For example,, by containingThere is the respective compound of acid or base groups to synthesize the officinal salt of bendamustine by conventional chemical method. Conventionally (example,As) these compounds by making free acid or free alkali form in water or in organic solvent or in the two mixture withStoichiometry reacts to prepare these salt with corresponding alkali or acid. Conventionally preferably such as ether, ethyl acetate, isopropyl alcohol or secondThe non-aqueous media of nitrile and so on. The sour example that can be used for the officinal salt that forms bendamustine comprises: inorganic acid, for example saltAcid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; And organic acid, for example acetic acid, maleic acid, fumaric acid, citric acid, grassAcid, butanedioic acid, tartaric acid, malic acid, lactic acid, pyrovinic acid and p-methyl benzenesulfonic acid. The officinal salt of bendamustine can deriveFrom inorganic base or organic base with produce ammonium salt, alkali metal salt (lithium, sodium, potassium etc.), such as the alkali salt such as calcium or magnesium, aluminium salt,Such as the low-grade alkylamine salt such as methylamine salt or ethylamine salt, low alkyl groups such as ethylenediamine salt diamine salts, ethanolamine salt, N, N-bis-Alkylidene ethanolamine salt, triethanolamine salt and glucose amine salt, and amino acid whose basic salt. Especially preferably by hydrochloric acid, hydrogen bromineAcid salt prepared by acid and hydroiodic acid, and hydrochloride is the officinal salt of most preferred bendamustine. Pass through the artIn known routine techniques prepare described pharmaceutically useful salt.
Expression way " its pharmaceutically useful solvate " refers to and is applied to patient's (directly or indirectly) so that bendamustine to be providedAny acceptable solvent compound in spit of fland. This term also comprises the acceptable solvent compound of bendamustine ester. Described solvateBe preferably hydrate, with alcohols (as methyl alcohol, ethanol, propyl alcohol or isopropyl alcohol) form solvate, with ester class (as acetic acid secondEster) form solvate, with ethers (as methyl ether, ether or THF(oxolane)) form solvate or with DMF(bis-NMF) form solvate, wherein, more preferably hydrate or with alcohols (as ethanol) form solvate. StructureThe solvent of solvate is preferably acceptable solvent.
Especially preferred, the active component in the present composition is bendamustine or its officinal salt. Most preferably, described active component is bendamustine hydrochloride.
In pharmaceutical composition, the dosage of active component can be by technical staff according to patient's situation, sex, body weight, body surfaceArea (m2; Average about 2m2/ people) or the age and easily determine, especially determine according to patient's body weight and body surface area.Preferably, every daily dose of active component is extremely about 1000mg of about 50mg, is preferably about 100mg to about 500mg, more preferablyAbout 200mg is about 400mg extremely, and most preferably is about 280mg. Every daily dose can be used or use with multiple dose with single dose,For example twice or three times of every day, most preferably be with every day single dose use. Described every daily dose can use once or one in one weekAll administered several times. Minimum single oral dose is 50mg. Above-mentioned dosage relates to bendamustine, and ester pharmaceutically useful with it,When salt or solvate are relevant, above-mentioned metering can easily be recalculated. Can represent dosage with absolute magnitude (mg), but swollenIn knurl, conventionally consider patient's body surface area and dose form is shown to mg/m2。
Maximum tolerated dose (MTD) and the effective dose of bendamustine depend on the cumulant that each cycle uses.According to the repeated BA(reproducibleBA of bendamustine), the each cycle cumulative measurement of MTD is up to 1000mg. OftenThe lower limit of effective intergal dose of cycle is between between 350mg to 500mg. Therefore, the each cycle intergal dose of 350mg to 1000mgNeed oral administration. The preferred oral intergal dose of each cycle is 500mg to 700mg. Can be with effective list of 50mg to 900mgDosage provides bendamustine. The preferable range of single oral dose is 200mg to 300mg.
The maximum tolerated dose (accumulation) of one-period (cycle in 3-4 week) is about 1000mg bendamustine. QuickIn sense/injured patient, the intergal dose of one-period (3-4 week) is about 350-500mg bendamustine, preferably at 4 weeksInterior is about 365mg.
May be with preferred oral dose scheme:
-is 200mg to 300mg in 1 day and the 2nd day, and optional is the low maintenance dose of 50mg afterwards, once a day.
-(comprised the 14th day) from the 1st day to the 14th day, every day 50mg bendamustine.
-Yue 150mg bendamustine, weekly, continues 3 weeks.
Conventionally, in treatment cycle, utilize bendamustine to treat to be effectively, wherein take bendamustine andOptional other reagent also continues 1 to 5 day, repeats this treatment subsequently after interrupting 2 to 4 weeks. Continue to repeat this treatment cycle,Until corresponding symptom to be treated improves. Substantially, the number of times of repetition is determined by doctor. Conventionally, this treatment cycle repeats 4To 15 times, preferably 4 to 12 times, more preferably 4 to 6 times.
Provide effective (intravenous administration) for specific adaptations card and preferred oral administration in the following scope of the inventionScheme:
Single therapy chronic lymphocytic leukemia:
Took 100mg/m at the 1st day and the 2nd day2The bendamustine hydrochloride of body surface area; Within every 4 weeks, once (vein is executedWith).
Oral: 145mg/m2Or 261mg (1.8m2): every day 100-200mg/m2Or 150-350mg.
The intractable inertia NHL of single therapy Rituximab:
At the 1st day and the 2nd day, 120mg/m2The bendamustine hydrochloride of body surface area; Every 3 weeks once (intravenous administration).
Oral: 174mg/m2Or 313mg (1.8m2): every day 100-250mg/m2Or 150-400mg.
Preferably, in first-line treatment NHL, by bendamustine and vincristine and Bo Nisong groupClose use.
Huppert's disease:
At the 1st day and the 2nd day, 120-150mg/m2The bendamustine hydrochloride (intravenous administration) of body surface area; At the 1st dayTo the 4th day, intravenous injection or oral administration 60mg/m2The Bo Nisong of body surface area, every 4 weeks once.
Oral: 174-217mg/m2Or 313-391mg (1.8m2): every day 100-250mg/m2Or 150-400mg.
First-line treatment suffers from the patient's of follicular lymphoma (FL), indolent lymphoma and lymphoma mantle cell (MCL) groupClose treatment:
Rituximab 375mg/m2(the 1st day)+bendamustine 90mg/m2(the 1st day+the 2nd day), every 28 days once (quietArteries and veins is used).
Oral: 130mg/m2Or 235mg (1.8m2): every day 100-200mg/m2Or 150-350mg.
Therefore, the present invention relates to defined pharmaceutical composition for the treatment of following medical science symptom for per os above, described inMedical science symptom is selected from chronic lymphocytic leukemia, ALL, chronic myelocytic leukemia, acute granulocyteLeukaemia, Hodgkin's disease, NHL, malignant lymphoma, breast cancer, oophoroma, ED-SCLC and non-little thinBorn of the same parents' lung cancer, wherein dosage regimen comprises: be at least 100mg/m at the 1st day and the 2nd day application dosage2/ people is to 600mg/m2/ people'sBendamustine, optionally, at intravenous injection in the 1st day to the 5th day or Orally administered 50mg/m2To 150mg/m2Cortex class solidAlcohol, and optionally use the other activating agent of suitable dose, this activating agent selects free CD20 specific antibody, anthracycline derivativeThe group of thing, vinblastine or platinum derivatives composition; And after interval 2-4 week, described dosage regimen is repeated 4 to 15 times.In addition, the present invention relates to definedly for the pharmaceutical composition of defined purposes above above, wherein active component benzene reachesMo Siting used with such dosage regimen, and described dosage regimen is selected from: used 200-300mg at the 1st day and the 2nd day; OptionallyUse once a day subsequently the maintenance dose of 50mg; (comprise the 14th day) from the 1st day to the 14th day, use 50mg every day; OrUse weekly 150mg, continue 3 weeks.
The invention still further relates to definedly for the pharmaceutical composition of defined purposes above above, wherein patient is for suffering fromHave the people of NHL, and dosage regimen comprises: used the work that total amount is 200mg/ people/sky at the 1st day to the 5th dayProperty composition bendamustine, the 1st day through intravenous administration 2mg vincristine, and the 1st day to the 5th day through intravenous administration 100mg/m2Prednisone, every three weeks repeat once described treatment, until NHL is taken a turn for the better.
The invention still further relates to definedly for the pharmaceutical composition of defined purposes above above, wherein patient is for suffering fromHave the people of Huppert's disease, and dosage regimen comprises: be 100-250mg/m at the 1st day and the 2nd day amount of application2SurfaceLong-pending, preferably 174-217mg/m2The bendamustine hydrochloride of body surface area, and the 1st day to the 4th day through vein or oral administration60mg/m2Prednisone, every surrounding repeats once described treatment, until above-mentioned Huppert's disease is taken a turn for the better.
The invention still further relates to definedly for the pharmaceutical composition of defined purposes above above, wherein patient is for suffering fromHave the people of chronic lymphocytic leukemia, and dosage regimen comprises: the 1st day and the 2nd day amount of application are 100-200mg/m2BodySurface area, preferably 145mg/m2The bendamustine hydrochloride of body surface area, and the 1st day to the 4th day through vein or oral administration60mg/m2Prednisone, every surrounding repeats once described treatment, until described chronic lymphocytic leukemia is taken a turn for the better.
The invention further relates to defined for the above pharmaceutical composition of defined purposes, wherein patient aboveFor suffering from the people of follicular lymphoma, indolent lymphoma or lymphoma mantle cell, and dosage regimen comprised: at the 1st day and the 2ndIt amount of application is 375mg/m2Rituximab, and at the 1st day and the additional 100mg/m that uses of the 2nd day per os2To 200mg/m2，Be preferably 130mg/m2Bendamustine, every 28 days repeat once, until corresponding lymthoma is taken a turn for the better.
Described formulation can comprise amount or its part amount of single dose every day. Preferably, formulation of the present invention comprises approximately10mg, to about 1000mg, is preferably about 25mg to about 600mg, more preferably extremely about 200mg of about 50mg, and most preferably be approximatelyThe active component of 50mg or about 100mg.
As used herein, term " non-ionic surface active agent " refers to have polarity hydrophilic radical and nonpolar lipophilic groupOr the amphiphilic compound of chain, and wherein, the hydrophilic and oleophilic properties of compound is with so-called hydrophilic-lipophilic balance (HLB) (HLB)Value characterizes. Preferably, for the preparation of the HLB value of the non-ionic surface active agent of the present composition between 10 and 20, morePreferably between 12 and 18. Described non-ionic surface active agent also has between 5 DEG C and body temperature (37 DEG C), be preferably justLower than fusing point, flow point or melting range (meltingrange) between room temperature (20 DEG C) and body temperature. Described material at room temperature can beLiquid state or semisolid. Described amphipathic nature material is the carrier of bendamustine active component, and this bendamustine active component canExist with dissolved form, suspended form or the form that is partly dissolved partial suspended.
Be advantageously used in the non-ionic surface active agent of preparing the present composition select free GREMAPHOR GS32 orThe group of its derivative and ethylene oxide/propylene oxide block copolymer composition, condition be these materials have aforesaid HLB value withFusing point, flow point or melting range.
In one embodiment, non-ionic surface active agent is GREMAPHOR GS32. GREMAPHOR GS32An example with trade nameSell. There is various purity and viscosityProduct is preparedAnd can be used for the present invention. Particularly, can use Cremophor RH40 (And poly-RH40)Oxygen ethene-35-castor oil (EL orELP). KnownELP andEL is as nonionic solubilizer and emulsifying agent, and it is by making castor oil and the oxirane mol ratio with 1:35React and prepare. Their HLB value be 12 to 24 and fusing point be 26 DEG C. According to environment temperature, can these products are fixedProperty is semisolid or medium viscosity liquid. Cremophor RH40 (withRH40 is commercially available) at 25 DEG CBe down semisolid material, and at same temperature, the shape of the aqueous solution that its range of viscosities is 20cps to 40cps(30%Formula). Known Cremophor RH40 is nonionic solubilizer and emulsifying agent. It is by making castor oil and epoxyEthane reacts and prepares with the mol ratio of 1:45. Its HLB value scope is 14 to 16, and melting range is 20 DEG C-28 DEG C.Test shows, Cremophor RH40 itself just can be advantageously used in preparation composition of the present invention.
Block copolymer is made up of ethylene oxide block and propylene oxide block. Described ethylene oxide unitThere is hydrophily, and propylene oxide units has lipophile. Hydrophilic ethylene oxide unit and the propylene oxide units of oleophylicNumber of variations causes copolymer to have different molecular weight and different hydrophilic-lipophilic balance (HLB) (HLB) value. HLB value and fusing point orFlow point or melting range meet expoxy propane (" PEO ")-PPOX (" the PPO ") block copolymerization of preparing present composition requirementThe example of thing comprises commercially available typeL35、L44、L64、P85 andP105。L44 or124, but be not68 or188 Hes127 or407。L44 is preferred non-ionic surfaceActivating agent.
Except Cremophor RH40, above-mentioned non-ionic surface active agent is such liquid, shouldThe viscosity number of liquid may be very low and can not avoids bendamustine hydrochloride to separate out. Another problem to be solved is to findSuch excipient or the combination of excipient, it makes the viscosity total value of mixture enough high to avoid bendamustine chlorideIn the time adding mixture, separate.
Therefore, the composition that comprises liquid nonionic surfactants of the present invention also advantageously comprises viscosity improver.Suitable viscosity improver comprises: powder, for example cataloid is (with trade nameCommercially available obtaining); Or partly solidBody wax material, for example LABRASOL is (with trade name44/14 commercially available obtaining). JoinPowder in liquid nonionic surfactants or the amount of semisolid material depend on the viscosity of liquid nonionic surfactants.After tested the suitable minimum of the viscosity improver that added to find of different concentration, thereby avoid visible activityOne-tenth analyzes. The relative concentration of the cataloid conventionally adding is approximately 1% to approximately 8%, is low to moderate 1.7% or 2.0% but be preferably,In order to avoid the dissolution characteristic of active component is had a negative impact. Conventionally the relative concentration of LABRASOL is 5%To 50%, and be preferably approximately 10% and approximately 45%.
Preferred composition of the present invention is open in embodiment 4, and comprises bendamustine hydrochloride and following materialCombination:
-Cremophor RH40;
-ethylene oxide/propylene oxide block copolymer (L44NF or124), it can be appointedSelection of land and cataloid or LABRASOL (44/14) combination, and
Polyoxyethylene-35-castor oil, its optionally with LABRASOL (44/14）Combination.
Advantageously, pharmaceutical composition of the present invention is packed in capsule, can makes like this patient be easy to take.
Conventionally use two kinds of capsules, and they can be divided into according to the character of capsule shell and pliability: soft capsule andHard shell capsules.
Soft capsule is the single unit solid dosage forms that comprises liquid or semi-solid filler. Adopt rotation stamping technique through a stepManeuver is shaped, is loaded and sealed. For many years, soft capsule is used as the unit-dose container of liquid always, and hard shell capsulesBe generally used for the solid of delivery of powered, particle and pill form. Hard shell capsules is single unit formulation, by the capsule cap of making respectively andCapsule body composition, and provide for loading with empty form.
The most typically, by adding gelatin to make flexible glue in plasticizer (being generally glycerine or sorbierite) and waterCapsule. Concerning hard shell capsules, the most frequently used polymer is also gelatin. Another kind of composition is the water that plays plasticizer effect. But, shouldComposition may cause the degraded of active component (for example bendamustine hydrochloride). Therefore, can be in addition by hydroxypropyl methyl fibreDimension is usually made hard shell capsules. Soft capsule and hard shell capsules also can comprise colouring agent and opacifier.
Preferred capsule type for composition of the present invention is hard shell capsules, and particularly more preferably is gelatin hardCapsule. It is desirable to, the material in capsule to be inserted is at room temperature fluid, and this can be avoided heating in the time of packing job. Conventionally, addHeat can cause active component easily to be degraded.
In principle, many kinds of excipient can be inserted to hard shell capsules, but except the consideration of biopharmacy aspect, finalThe chemical stability of formulation and physical stability, and prepare the required stripping behavior of safe, effective and stable formulation and be alsoNeed the emphasis of considering.
Conventionally, for the preparation of filled hard capsules can be Newtonian liquid (for example the gel of oil, thixotropy or shear shinning,Or semisolid matrix product), it is carried out to filling at elevated temperatures, and active component is dissolved in wherein or with meticulous pointThe form of a prose style free from parallelism is suspended in wherein. In principle, can use the mixture of any excipient or excipient, as long as packing materialViscosity reaches the requirement of filling process. The uniformity of capsule filling weight is very important. In addition, filling preparation should not showGo out wire drawing, and should be able to separate neatly with quantitative ozzle (dosingnozzle).
Find unexpectedly the combination that can advantageously use with snap fit capsule first embodiment of the inventionThing. If will select free GREMAPHOR GS32 or derivatives thereof and ethylene oxide/propylene oxide block copolymer to formGroup, particularly select free Cremophor RH40, polyoxyethylene-35-castor oil andL44 orSpecific non-ionic surface active agent in the group of 124 compositions and bendamustine or its pharmaceutically useful ester,Salt or solvate blending, and after blending, be filled into snap fit capsule, can realize good stability, good moltenTrip is and good bioavilability. On the contrary, compared with only comprising the composition of Cremophor RH40, asFruit by Cremophor RH40 with such as two-bis-many acyl groups of glycerine adipate ester-1(with trade name645 commercially available obtaining) and ethylene oxide/propylene oxide block copolymer (with trade nameL44NF orPoloxamer124 is commercially available to be obtained)) fluent material be used in combination, the stripping behavior meeting of bendamustine is deteriorated. In addition need,It is to be noted, can not be byA25(ceteareth-25(ceteareth-25) or polyethylene glycol(25) cetearyl alcohol ether) andA6(ceteareth-6 and stearyl alcohol or polyethylene glycol (6) cetearyl alcoholEther) as non-ionic surface active agent. Other excipient that is generally used for preparing liquid filling capsule preparations also demonstrates and does not haveGratifying result is provided.
In addition, composition of the present invention can comprise additional excipient, particularly protective agent, for example antioxidant and anti-Bacterium anticorrisive agent, for example methyl hydroxybenzoate, ethyl hydroxy benzoate and the Nipasol of example in embodiment 1 to 3. Antioxidant can be d-α-Tocopherol acetate, dl-alpha-tocopherol, ascorbyl palmitate, butylated hydroxyanisol (butylatedHydroxyanidole), ascorbic acid, butylated hydroxy anisole, butylhydroxy quinone, BHA, hydroxycoumarin, fourthHydroxy toluene, progallin A, n-propyl gallate, octyl gallate, dodecyl gallate or their mixture. ExcellentChoosing adds antioxidant in the composition that comprises Cremophor RH40 or polyoxyethylene-35-castor oil.
Sugar exists in a large number in the composition described in second embodiment of the invention, and its amount is preferably active material weight2 times to 5 times. In the time sugar being introduced in composition of the present invention, it demonstrates has positive effect to the stability of reactive compoundShould. In addition, find unexpectedly, with compared with capsule, these excipient make particularly hydrochloric acid of reactive compoundThe bioavilability of bendamustine increases.
The preferred example of described sugar comprises sweet mellow wine, maltitol, antierythrite, xylitol, lactose, sucrose, grapeSugar, sorbierite, maltose, trehalose, lactitol and dextrose (anhydrous or monohydrate).
Except these sugared excipient, pharmaceutical composition of the present invention can comprise other excipient, as carried out more belowThe lubricant, glidant, filler (or diluent), adhesive and the disintegrant that describe in detail.
Lubricant is to have following one or more of functions in the preparation process of pharmaceutical composition especially tabletMaterial: prevent that tablet material is adhered to tablet press machine parts (hopper, pressing mold and drift) surface, reduces interparticle friction, makesTablet is easy to from pressing mold discharge and improves the flow rate of mixture (treating compressing tablet). Described lubricant selects free tristearin conventionallyAcid, stearate or stearate, hydrogenated vegetable oil, magnesia, polyethylene glycol, lauryl sodium sulfate and talcum and itThe group of compositions of mixtures. Described lubricant is preferably selected from dolomol, calcium stearate, zinc stearate, stearic acid palmitic acidGlyceride and sodium stearyl fumarate and their mixture. Stearic acid is optimum selection.
In this application, term glidant is understood to be to improve the material of the flowing property for the treatment of press sheet mixture. ForGlidant, can use any suitable glidant, for example talcum, silica and silica gelStarch and calcium silicates. Conventionally use silica.
Conventionally, term filler (or diluent) represents that those are for increasing the excipient for the treatment of compressing tablet material volume. ThisThe increase of size has improved the processing to solid composite. If the dosage of every part of solid composite Chinese traditional medicine is low, solid in other wordsVery little, filler is normally necessary so for body composition. The example of suitable filler is lactose, sucrose (sucrose), sweetReveal alcohol, sorbierite, cane suger (saccharose), starch, pregelatinized starch, microcrystalline cellulose, powdery cellulose, phosphoric acid hydrogenCalcium, calcium carbonate and their any combination. In preferred embodiments, described filler selects free lactose, starch, crystalliteThe group of cellulose, fine cellulose and their any combination composition, most preferably is Lactis Anhydrous and microcrystalline cellulose.
Conventionally, term adhesive is used for giving pharmaceutical preparation caking property, and this caking property ensures that described composition keeps complete(the especially tablet after compression forming). According to used compact technique (direct pressing, non-slurry pelletizing or wet granulation)Use different adhesives. For dry method compact technique (direct pressing and non-slurry pelletizing), suitable adhesive be lactose,Sucrose, sweet mellow wine, sorbierite, cane suger, starch, pregelatinized starch, microcrystalline cellulose, powdery cellulose, calcium monohydrogen phosphate, carbonAcid calcium and their any combination. In preferred embodiments, described adhesive selects free lactose, starch, microcrystalline celluloseThe group of element, fine cellulose and their any combination composition, most preferably is Lactis Anhydrous and microcrystalline cellulose. Make in wet methodIn grain process, adhesive both can be used as solution and had used, and also can use with the form being dried. As suitable adhesive, hereThat can mention has (for example) polyvinylpyrrolidone, dispersibles cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, firstBase cellulose, starch, pregelatinized starch, partially pregelatinized starch, gum arabic, dextrin, amylopectin etc. Sticky at theseIn mixture, more preferably dispersible cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
In pharmaceutical composition, especially in tablet composition, can comprise disintegrant, so that tablet and moisture physiological liquid are connectBe easy to after touch decompose or disintegration. In the time of swallow tablet, disintegrant is for example responsible for, conventionally at tablet and body fluid (saliva, gastric juice and intestinesRoad liquid) make the quick disintegration of tablet after contact. The material as disintegrant is divided into starch based, fibre according to chemical propertyTie up plain class, cross-linked polymer class etc. Kind and the addition thereof of the disintegrant using time of the present invention to enforcement are studied, knotFruit is found starch, modified starch (for example Explotab), sodium carboxymethylcellulose, cross-linked carboxymethyl fibreTie up plain sodiumPVPP, bohr Acree woods sylvite (polacrilinpotassium）（IRP88) and low-substituted hydroxypropyl cellulose can produce extraordinary disintegration effect.
The stability of the bendamustine aqueous solution is subject to the strong effect of pH value. In the time that pH value is greater than approximately 5, observe this chemical combinationA large amount of hydrolysis of thing. When pH value > 5 time, decompose and carry out rapidly and within the scope of this pH value, the content of gained accessory substance is high. MainThe hydrolysate of wanting is 4-[5-[(2-chloroethyl)-(2-ethoxy) amino]-1-methyl-benzimidazolyl-2 radicals-yl]-butyric acid(HP1), 4-[5-[bis-(2-ethoxy) amino]-1-methyl-benzimidazolyl-2 radicals-yl]-butyric acid (HP2) and 4-(5-morpholinyl-1-Tolimidazole-2-yl)-butyric acid (HP3):
The medicine of oral administration absorbs conventionally in stomach, small intestine and/or large intestine. PH value in stomach is approximately 1 to 3.5,In small intestine, be approximately 6.5 to 7.6, and in large intestine, be approximately 7.5 to 8.0. Therefore, for as bendamustine pH value higher thanThe compound that tends to degraded in 5 aqueous environments, it is highly preferred that it is absorbed under one's belt, and do not drain into littleIntestines, large intestine even, decompose avoiding. Therefore need such pharmaceutical composition, bendamustine wherein under one's belt completely orBe absorbed at least to a great extent, thereby avoid or reduce bendamustine in small intestine or the degraded in large intestine.
Find unexpectedly, can be by adopting pharmaceutical composition of the present invention to solve described problem. TheseAt pharmaceutically acceptable excipient, (it is to select free GREMAPHOR GS32 or derivatives thereof and oxirane and expoxy propaneNon-ionic surface active agent in the group of block copolymer composition) in comprise bendamustine hydrochloride composition ground beyond expectationDemonstrate Fast Stripping, particularly, its stripping situation is: through using according to European Pharmacopoeia the oar formula device that rotating speed is 50rpmIn simulated gastric fluid, measure, bendamustine stripping at least 60% in 20 minutes, stripping at least 70% in 40 minutes, and 60Stripping at least 80% in minute, and preferably stripping at least 60% in 10 minutes, stripping at least 70% in 20 minutes, and 30Stripping at least 80% in minute. Simulated gastric fluid used herein refers to 2g sodium chloride is dissolved in to 1000ml water, then adjusts with 5N hydrochloric acidSave pH value to 1.5 ± 0.05 and the solution of preparation.
In addition,, in the time that said composition is carried out to accelerated stability test, it demonstrates is stable. This is unexpected, because test demonstrates:
-in snap fit capsule, only comprise bendamustine hydrochloride with reference to (seeing reference example 1) capsule preparations,In the time preserving at (vial is opened) and 50 DEG C under 40 DEG C/75%RH, form catabolite preserving within one month. ?40 DEG C and 75%RH(relative humidity) and open in the situation of bottle, the amount of hydrolysate HP1 increases by 4 after preserving one monthDoubly. For the bottle of sealing, the content of HP1 is even higher.
-in the capsule preparations situation of reference example 2,3 and 4, in the time that under 40 DEG C/75%RH, (closed glass bottle) preserved,Form catabolite preserving within one month, and it increases with further preservation.
Medicine is drained into small intestine total time by stomach between approximately 20 minutes to 5 hours between, conventionally between approximately 30 minutes to 3 littleTime between. Therefore, pharmaceutical composition of the present invention can advantageously reduce the degraded of bendamustine in patient body, because whereinBendamustine be what to discharge under one's belt with stripping to a great extent. Therefore, can anticipate that the benzene that comprises of the present invention reachesThe composition of Mo Siting even has the bioavilability of improvement.
In another aspect of the present invention, can use the treatment of described combination of oral medication or the prevention mankind orThe recurrence of animal (being preferably the mankind) traditional Chinese medicine symptom, described medical science symptom is selected from chronic lymphocytic leukemia and (is abbreviated asCLL), ALL (being abbreviated as ALL), chronic myelocytic leukemia (being abbreviated as CML), the white blood of acute granulocyteSick (being abbreviated as AML), Hodgkin's disease, NHL (being abbreviated as NHL), Huppert's disease, breast cancer, oophoroma,ED-SCLC, non-small cell lung cancer and autoimmune disease.
In another aspect of the present invention, described pharmaceutical composition as solid dosage form can be used for the treatment of, induce, rob treatmentTreat, pretreatment before stem cell transplantation, maintain treatment, treatment to human or animal's (being preferably people) medical science symptom Residual Disease, described inMedical science symptom is selected from chronic lymphocytic leukemia (CLL), ALL (ALL), chronic myelocytic leukemia(CML), acute myeloblastic leukemia (AML), Hodgkin's disease, NHL (NHL), Huppert's disease, breast cancer,Oophoroma, ED-SCLC, non-small cell lung cancer and autoimmune disease.
The present invention also comprises treatment human body or animal body traditional Chinese medicine symptom or prevents the method for described medical science symptom recurrence, is somebody's turn to doMethod comprises to the pharmaceutical preparation of the present invention of using effective dose in the human body of needs treatments or animal body, described medical science symptomBe selected from chronic lymphocytic leukemia, ALL, chronic myelocytic leukemia, acute myeloblastic leukemia,Hodgkin's disease, NHL, Huppert's disease, breast cancer, oophoroma, ED-SCLC, non-small cell lung cancer andAutoimmune disease. Preferred medical science symptom is NHL.
In another aspect of the present invention, described pharmaceutical composition can be used with at least one other activating agent combination,Wherein, described other activating agent before using described pharmaceutical composition, simultaneously or administration afterwards. Described at least oneOther activating agent is preferably CD20 specific antibody (for example Rituximab or Ao Fate order monoclonal antibody (ofatumumab)), anthracene nucleusDerivative (for example adriamycin or daunorubicin), vinblastine (for example vincristine), platinum derivatives (for example cis-platinum or carboplatin),Da Polinai (FK866), YM155, Thalidomide and analog thereof (for example lenalidomide (lenalidomide)) or proteaseBody inhibitor (for example bortezomib (bortezumib)).
Pharmaceutical composition of the present invention also can with at least one corticosteroid combined administration, wherein, described corticosteroidBefore using described pharmaceutical composition, simultaneously or administration afterwards. The example of described corticosteroid is prednisone, sprinklesNi Songlong and dexamethasone.
Some dosage regimens are feasible. For example, in the patient who suffers from NHL, administration as follows: 1-5 days withOral formulations is used the bendamustine that total amount is 200mg/ people/sky+1st day through intravenous administration 2mg vincristine+the 1-5 daysThrough intravenous administration 100mg/m2Prednisone, every 3 weeks once. In the patient who suffers from MM, administration as follows: at the 1st day and the 2ndIt taking oral formulations use total amount as bendamustine+the 1-4 days of 400-500mg/ people/sky through vein or oral administration60mg/m2Prednisone, every 4 weeks once. In the patient who suffers from CCL, administration as follows: at the 1st day and the 2nd day, with oralPreparation is used the bendamustine that total amount is 200-300mg/ people/sky, and every 4 weeks once+1-4 days through vein or oral administration60mg/m2Prednisone, every 4 weeks are once.
Being also advantageous in that of liquid filling snap fit capsule of the present invention, do not need for active component (its optionally withOne or more mixed with excipients) dressing be set further cover the taste of described active component, and/or described in protectionActive component is not for example subject to, by illumination and/or the caused possible adverse effect of moisture (be oxidized, degrade), or prevents from being controlledPerson's mucous membrane of mouth is owing to interacting and wrecking with active component.
Come by following example that further the present invention will be described. Apparent for a person skilled in the artThat these examples are only the objects of signal, and should not thought to limit the present invention.
Example
A) relate to the example of the first embodiment of the present invention
1. capsule preparations
Reference example 1: bendamustine capsule preparations (prior art)
Weigh 20.0 ± 1mg bendamustine hydrochloride and pack in the capsule body of sky snap fit capsule, put into afterwards transparent glassIn Agilent (Agilent) the HPLC bottle (6ml) of glass system. By capsule cap being placed on capsule body and light pressure with by glueBe encapsulated and close.
Capsule is kept under 40 DEG C/75%RH at (vial is opened) or 50 DEG C (vial sealing). Use HPLC(pillar: ZorbaxBonus-RP, 5 μ m; Column oven temperature: 30 DEG C; Auto injection actuator temperature: 5 DEG C; Detector: 254nm) surveyThe content of amount bendamustine hydrochloride and related substances. Result is shown in table 1:
*1:NP1:4-[6-(2-chloroethyl)-3,6,7,8-tetrahydrochysene-3-methyl-imidazoles [4,5-h]-[Isosorbide-5-Nitrae] benzothiazine-2-yl] butyric acid
BM1 dimer: 4-{5-[N-(2-chloroethyl)-N-(2-{4-[5-bis-(2-chloroethyl) amino-1-methyl benzo miaowAzoles-2 base] butyryl acyloxy } ethyl) amino]-1-tolimidazole-2 base } butyric acid
BM1EE:4-[5-[bis-(2-chloroethyl) amino]-1-methyl-benzimidazolyl-2 radicals-yl] ethyl butyrate
*2:n.d.: cannot detect, that is, exceed detectability (area percentage is less than 0.05%)
Reference example 2
For the batch of 1000 capsules, all excipient except cataloid and stearic acid are all filledEnter Somakon container (5L). Add bendamustine and mix 4 minutes (wiper (wiper) 10rpm) with 1000rpm.By 0.5mm screen cloth, gained mixture is sieved. Mixture is reloaded to described container, and add cataloid.Mix under these conditions 2 minutes. Add afterwards stearic acid and continue and mix 1 minute. Passing through subsequently 0.5mm screen cloth willMixture sieves, and reloads described container and mixes 30 seconds again, and mixing condition is all identical with above-mentioned condition.
Described mixture is transferred to capsule filler (ZanassiAZ5) and inserts respectively snap fit capsule (size 2)(average quality: 259.5mg(is initial)-255.3mg(is final)) and Hydroxypropyl methylcellulose capsule (size 2) (average quality:255.8mg(is initial)-253.4mg(is final)). In the vial of sealing, under 40 DEG C/75%RH, preserve capsule. Use HPLC(pillar: ZorbaxBonus-RP, 5 μ m; Column oven temperature: 30 DEG C; Auto injection actuator temperature: 5 DEG C; Detector: 254nm) surveyThe amount of amount bendamustine hydrochloride and the related substances such as catabolite, synthetic accessory substance. Result is filled out at table 2b(Enter in Hydroxypropyl methylcellulose capsule) and show 2c(and insert in gelatine capsule) shown in.
*3: for main peak, the not clear compound peaks under 0.65 relative retention time
Reference example 3
For 1000 capsules, all excipient except cataloid and stearic acid are all packed intoSomakon container (5L). Add bendamustine and mix 4 minutes (wiper 10rpm) with 1000rpm. Pass through 0.5mmScreen cloth sieves gained mixture. Mixture is reloaded to described container, and add cataloid. In above-mentioned conditionUnder mix 2 minutes. Add afterwards stearic acid and continue and mix 1 minute. Pass through subsequently 0.5mm screen cloth by mixture mistakeSieve, reloads described container and mixes 30 seconds again, and mixing condition is all identical with above-mentioned condition.
Described mixture is transferred to capsule filler (ZanassiAZ5) and inserts respectively snap fit capsule (size 2)(average quality: 257.9mg(is initial)-255.2mg(is final)) and Hydroxypropyl methylcellulose capsule (size 2) (average quality:261.1mg(is initial)-257.8mg(is final)). In the vial of sealing, under 40 DEG C/75%RH, preserve capsule. As above instituteState, measure the amount of bendamustine hydrochloride and related substances with HPLC. Result is inserted in Hydroxypropyl methylcellulose capsule at table 3b()3c(inserts in gelatine capsule with table) shown in.
Reference example 4
For 1000 capsules, all excipient except cataloid and dolomol are all packed intoSomakon container (2.5L). Add bendamustine and mix 4 minutes (wiper 10rpm) with 1000rpm. Pass through0.5mm screen cloth sieves gained mixture. Mixture is reloaded to described container, and add cataloid. UpperState under condition and mix 2 minutes. Add afterwards dolomol and continue and mix 1 minute. To mix by 0.5mm screen cloth subsequentlyCompound sieves, and reloads described container and mixes 30 seconds again, and mixing condition is all identical with above-mentioned condition.
Described mixture is transferred to capsule filler (ZanassiAZ5) and inserts respectively snap fit capsule (size 2)(average quality: 241.3mg(is initial)-244.mg(is final)) and Hydroxypropyl methylcellulose capsule (size 2) (average quality:243.5mg(is initial)-243.mg(is final)). In the vial of sealing, under 40 DEG C/75%RH, preserve capsule. As above instituteState, measure the content of bendamustine hydrochloride and related substances with HPLC. Result is inserted Hydroxypropyl methylcellulose capsule at table 4b(In) and show 4c(and insert in gelatine capsule) shown in.
Embodiment 1
Weigh 0.68g methyl hydroxybenzoate, 0.068g Nipasol and 0.068g butylated hydroxytoluene and be dissolved in 6.14g ethanolIn. By enoughRH40 melts at 40 DEG C. Weighing 5.56g gained ethanolic solution, 36.83g fusingRH40 and 202.82gL44NF, and with mechanical agitator with 800rpm mix until mixThing bleach. By described mixture is placed in 10 DEG C so that its solidify. By hand operated mixing, 24.80g hydrochloric acid benzene is reached subsequentlyMo Siting adds in the mixture solidifying, afterwards with UltraturraxT18 high speed homogenizer with 15500rpm homogenizing 10 minutes,So that bendamustine hydrochloride is distributed in described mixture equably. The CFS1200 capsule charge that is used in operation at 25 DEG C is closeThe suspension of homogenizing is filled into snap fit capsule by envelope machine. By closed and sealed described capsule. At the vice of having of sealingIn amber glass bottle, under 40 DEG C/75%RH, under 30 DEG C/65%RH, under 25 DEG C/60%RH and preserve the liquid of gained at 5 DEG CBody filled capsules. Use HPLC(pillar: ZorbaxBonus-RP, 5 μ m; Column oven temperature: 30 DEG C; Auto injection actuator temperature: 5DEG C; Detector: 254nm) measure bendamustine hydrochloride and the related substances such as catabolite, synthetic byproductAmount. Result is shown in table 5b.
Embodiment 2
Weigh 0.68g methyl hydroxybenzoate, 0.068g Nipasol and 0.068g butylated hydroxytoluene and be dissolved in 6.14g ethanolIn. By enoughRH40 melts at 40 DEG C. Weighing 5.56g gained ethanolic solution and 239.65g fusingRH40, and mix until mixture bleach with 800rpm with mechanical agitator. Mixture is solidified also coldBut to room temperature. By hand operated mixing, 24.80g bendamustine hydrochloride is added subsequently to the mixture solidifying, Zhi HouyongUltraturraxT18 high speed homogenizer, with 15500rpm homogenizing 10 minutes, makes bendamustine hydrochloride be distributed in equably instituteState in mixture. The suspension of homogenizing is filled into gelatin hard by the CFS1200 capsule charge sealer that is used in operation at 40 DEG CCapsule. By closed and sealed described capsule. In the amber glass bottle with vice of sealing, under 40 DEG C/75%RH, 30DEG C/65%RH under, preserve the above liquid filling capsule obtaining under 25 DEG C/60%RH and at 5 DEG C. As mentioned above, survey with HPLCThe amount of amount bendamustine hydrochloride and the related substances such as catabolite, synthetic accessory substance. Result is shown in table 6bGo out.
Embodiment 3
Weigh 0.68g methyl hydroxybenzoate, 0.068g Nipasol and 0.068g butylated hydroxytoluene and be dissolved in 6.14g ethanolIn. By enoughRH40 melts at 40 DEG C. Weighing 5.56g gained ethanolic solution, 36.83g fusingRH40 and 202.82g645, and mix with 800rpm until mixture change with mechanical agitatorTransparent. By described mixture being placed at 10 DEG C so that its solidify. By hand operated mixing, 24.80g hydrochloric acid benzene is reached not subsequentlyDepartment spit of fland adds the mixture solidifying, afterwards with UltraturraxT18 high speed homogenizer with 15500rpm homogenizing 10 minutes, make saltAcid bendamustine is distributed in described mixture equably. The CFS1200 capsule charge sealer that is used in operation at 30 DEG C willThe suspension of homogenizing is filled into snap fit capsule. By closed and sealed described capsule. There is the amber of vice in sealingIn vial, under 40 DEG C/75%RH, under 30 DEG C/65%RH, under 25 DEG C/60%RH and preserve the liquid filling of gained at 5 DEG CCapsule. As mentioned above, measure bendamustine hydrochloride with HPLC and related substanceses such as catabolite, synthetic accessory substanceAmount. Result is shown in table 7b.
Embodiment 4
2. disintegration and dissolution test
Embodiment 5
Use the disintegration device A of operation at 37.0 DEG C ± 0.5 DEG C, in the buffering of 1000.0ml, pH value=1.0 ± 0.05In liquid, the liquid filling capsule preparations in embodiment 1,2 and 3 is carried out to slaking test. Result is listed in table 8a, 8b and 8c.
Embodiment 6
In the artificial hydrochloric acid in gastric juice solution that is 1.5 in pH value, the liquid filling capsule preparations of embodiment 1,2 and 3 is carried out to strippingTest (referring to European Pharmacopoeia PhEur:2.9.3: solid dosage forms is at the dissolution test of recommending in dissolution medium).
Stripping sample is tested to analyze (pillar: ZorbaxBonus-RP, 5 μ m by HPLC; Column oven temperature:30 DEG C; Auto injection actuator temperature: 5 DEG C; Detector: 254nm). Prepare by the following method simulated gastric fluid (pH value 1.5): willThe 0.2M potassium chloride (0.2M) of 250.0ml adds in 1000ml volumetric flask, adds the 0.2M hydrochloric acid of 207.0ml, Zhi HouyongMilli-Q water is diluted to 1000ml. If needed, pH value determination use 2N hydrochloric acid or 2N potassium hydroxide adjusting pH value to 1.5 ±0.05。
According to chapters and sections 2.9.3 in European Pharmacopoeia 6.0, operative installations 2(oar formula device) carry out dissolution test. Paddle board rotating speed is50rpm, temperature is 37 DEG C ± 0.5 DEG C, the amount of dissolution medium is 500ml.
The test result of the liquid filled hard capsules of embodiment 1,2 and 3 is shown in table 9a, 9b and 9c:
Can be learnt to only have the liquid filled hard capsules preparation of the embodiment of the present invention 2 to demonstrate by above-mentioned table 9a, 9b and 9cPreferred bendamustine Fast Stripping behavior below, that is: through being used the oar formula device that rotating speed is 50rpm to exist according to European PharmacopoeiaIn 500ml simulated gastric fluid, measure, bendamustine stripping at least 60% in 10 minutes, stripping at least 70% in 20 minutes,Stripping at least 80% in 30 minutes.
Embodiment 7
Table 10: the analytical test result of the preparation to embodiment 4
3. in vivo studies
Embodiment 8
The liquid filled hard of the embodiment 2 that male and female beagle oral administration is contained to 50mg bendamustineCapsule, and comparing with the capsule of reference example 1, with determine 1 dosage (being 50mg) bendamustine bioavilability (AUC andAnd the bioavilability fluctuating level of these capsule preparations (being the %CV of AUC and Cmax) Cmax). Described test also comprises otherPreparation (formulation X), but due to said preparation not within the scope of the present invention, therefore detailed description is not provided. Required animal number is16. Fundamental test is designed to the cross-over design (cross-overdesign) of 8 animals of each branch (arm).
1 phase (capsule of single dose, first day)
There is the wash-out phase (wash-outperiod) of one week.
2 phases (one week afterwards 1 phase, following every kind of preparation of single dose, the 8th day)
The average blood plasma of the liquid filling capsule preparations of capsule preparations (reference example 1) and embodiment 2 distributed with respect to the timeRelation be shown in Fig. 1.
Embodiment 9
Carry out evaluating the open mark of the absolute bioavailability of oral bendamustine in cancer patient's bodyRandom bidirectional crossed research, to evaluate the absolute biological profit of the bendamustine (embodiment 2) used with oral formulations formExpenditure. Except evaluating after oral administration and intravenous administration, outside the pharmacokinetics of bendamustine in blood plasma, objectAlso be to evaluate after the preparation of intravenous administration, especially oral administration embodiment 2 security of bendamustine and toleranceProperty.
6 patients carry out the treatment of two phases in hospital: the 1st day to the 2nd day (1 phase) and the 7th day were to the 9th day (2 phase). Storage patientWith two kinds of one in treating below the 1st day and the 8th day are accepted with random order:
The 110.2mg(2x55.1mg of-mono-oral dose) hydrochloric acid (HCl) bendamustine, it is equivalent to about 100mg benzene and reachesMo Siting free alkali, and
The 100mg bendamustine hydrochloride of-mono-intravenous injection dosage, it is equivalent to 90.7mg bendamustine free alkali.
Select salt according to the security of the security of oral formulations in preclinical study and registered intravenous administration preparationThe dosage (intravenous administration dosage is 100mg, and oral administration dosage is 110.2mg) of acid bendamustine.
Gathered blood sample with mensuration oral administration with after intravenous administration at the 1st day, the 2nd day, the 8th day and the 9th dayBendamustine and metabolin thereof the pharmacokinetics in blood plasma. According to the data selection warp in document (Preiss1985)Time point after intravenous administration bendamustine. Preiss and its colleague report, to cancer patient's oral administration dosage beAfter the bendamustine of the capsule form of 250mg to 350mg, the average bioavilability of bendamustine is 57%(scope:25% to 94%; %CV=44%). The 1st day morning and the 8th day morning per os or through the bendamustine (warp of intravenous administration single doseIntravenous administration 100mg or oral administration 110.2mg bendamustine hydrochloride).
Take the bendamustine of two liquid filling hard-shell capsule forms with the 250ml mouth of a river, or with venous transfusion 30 minutesForm use bendamustine.
Per os or before intravenous administration bendamustine in the morning, except can drinking water (until grind usingStudy carefully medicine two hours before), needs of patients overnight fasting at least 8 hours. After each administration 2 hours, patient can enterEat a small amount of breakfast.
Do not comprise following up a case by regular visits to after screening and research, total time administration phase is that (the 1st day to the 2nd day and the 7th day were to the 9th in 6 daysMy god).
Patient, using for the first time in the last fortnight of the first drugs, forbids taking some drugs.
Evaluate the haemoconcentration-time graph obtaining after 6 patients shown in Figure 2. With formula AUCPer os/ dosage/AUCThrough veinThe absolute bioavailability mean value that/dosage * 100% calculates is 58.5%, and standard deviation is 9.3, and poor between individualityDifferent (representing taking %CV) is 15.9.
Therefore, observe the bioavilability of the bendamustine hydrochloride in embodiment 2 oral formulations and document before(Preiss) capsule that contains bendamustine of report is consistent, but between patient, difference reduces greatly.
B) relate to the example of the second embodiment of the present invention
1. compatibility test
Embodiment 10a
Preparation comprises 1:1(mass/mass) bendamustine hydrochloride and the compatibility test mixture of excipient. InstituteState excipient and be selected from sweet mellow wine and lactose. After preparation, mixture is packed into Agilent (Agilent) HPLC of clear glass systemIn bottle (6ml), and preserve under the different preservation conditions as shown in table 11 below. On limited time point, by sampleProduct take out and check purity (HPLC, pillar: ZorbaxBonus-RP, 5 μ m from preservation condition; Column oven temperature: 30 DEG C; FromMoving injector temperature: 5 DEG C; Detector: 254nm) and outward appearance.
Table 11: preservation condition
*Before preserving at 70 DEG C, at 50 DEG C, preserve one month
**Before 40 DEG C/75% time preservation, under 25 DEG C/60%r.h., preserve one month
In all these mixtures, for all these three kinds of preservation conditions, the content of bendamustine hydrochloride (utilizesHPLC detects) almost do not change, remain on 99% always. For all these three kinds of preservation conditions, almost do not detectHydrolysate HP1(area % < 0.2).
With the naked eye described bendamustine hydrochloride mixture is carried out to outward appearance detection. All detected mixtures all meetSpecification, and all present while detecting while detecting immediately and preserve one month under all three kinds of preservation conditions after after preparationFor white is to pale powder.
Embodiment 10b
For the further method according to embodiment 1a is carried out compatibility test, preparation comprises 1:1(mass/mass) saltThe mixture of acid bendamustine and excipient. Described excipient is selected fromEPO, carboxymethyl fibreTie up plain sodium (And PVPP (Crospovidone) RC591).
UsingIn the situation of EPO, impurity HP1(hydrolysate) and the primary quantity of BM1DIMER increaseAdd (HP1:1.5%, BM1 dimer: 1%), but getting rid of under all preservation conditions of humidity effect, these impurity can be detectedIn preservation process, reduce. In the situation of use PVPP, the guarantor who opens at 40 DEG C/75%R.H./bottleDeposit under condition, can detect that HP1 is significantly increased to 0.4% by 0.1%. Under all other preservation conditions (bottle sealing),The increase of HP1 do not detected.
Under the preservation condition of 70 DEG C/bottle sealing, compriseThe mixture of EPO and comprise crosslinked polyethyleneThe outward appearance of the mixture of pyrrolidones changes. Two kinds of mixtures all become sticky slightly. In addition, comprise crosslinked polyethylene pyrrolidinesThe color of the mixture of ketone becomes cream color from white.
Under the preservation condition of 70 DEG C/bottle sealing, compriseMixture and compriseRC591'sThe color of mixture also becomes cream color.
2. tablet formulation
Embodiment 11
By mixing and within 15 minutes, prepare 253g mixture, this mixture in the cube agitator (Erweka) of 1 literThe sweet mellow wine (as main excipient) that comprises relative amount shown in following table 2a and microcrystalline cellulose,ColloidSilica, talcum and stearic acid. The screen cloth that passes through 0.425mm is afterwards by 10.612g mixture and 3.0g bendamustine hydrochlorideSieving in spit of fland, is transferred to subsequently in the Turbula blender T2A that is equipped with 50ml vial, and under 60rpm, mixes afterwards10 minutes.
Be the circular tablet with following characteristics by the mixture compression forming of gained:
Average diameter: 9.1mm; Average quality: 247.7mg; Average hardness: 81N.
Under 40 DEG C/75%RH (vial is opened) or at 50 DEG C (vial sealing) preserve tablet. Adopt HPLC(pillar: ZorbaxBonus-RP, 5 μ m; Column oven temperature: 30 DEG C; Auto injection actuator temperature: 5 DEG C; Detector: 254nm) surveyThe amount of amount bendamustine hydrochloride and the related substances such as catabolite, synthetic accessory substance. Result is in table 12bIllustrate.
*1:NP1:4-[6-(2-chloroethyl)-3,6,7,8-tetrahydrochysene-3-methyl-imidazoles [4,5-h]-[Isosorbide-5-Nitrae] benzothiazine-2-yl] butyric acid
BM1 dimer: 4-{5-[N-(2-chloroethyl)-N-(2-{4-[5-bis-(2-chloroethyl) amino-1-methyl benzo miaowAzoles-2 base] butyryl acyloxy } ethyl) amino]-1-tolimidazole-2-yl } butyric acid
BM1EE:4-[5-[bis-(2-chloroethyl) amino]-1-methyl-benzimidazolyl-2 radicals-yl] ethyl butyrate
*2:n.d.: cannot detect, that is, exceed detectability (area percentage is less than 0.05%)
Embodiment 12
Compound and relative quantity described in use following table 3a, by preparing mixture with method identical described in embodiment 11And tablet.
Described tablet has following characteristics:
Average diameter: 9.1mm; Average quality: 248.9mg.
Under 40 DEG C/75%RH (vial is opened) or at 50 DEG C (vial sealing) preserve tablet. As above instituteState, measure the content of bendamustine hydrochloride and related substances with HPLC. Result is shown in table 3b:
Embodiment 13
Compound and relative quantity described in use following table 14a, by preparing tablet with method identical described in embodiment 11.
Described tablet has following characteristics:
Average diameter: 9.1mm; Average quality: 247.8mg.
Under 40 DEG C/75%RH (vial is opened) or at 50 DEG C (vial sealing) preserve tablet. As above instituteState, measure the amount of bendamustine hydrochloride and related substances with HPLC. Result is shown in table 14b:
Prior art reference example
Weigh 20.0 ± 1mg bendamustine hydrochloride and pack in the capsule body of sky snap fit capsule, put into afterwards transparent glassIn Agilent (Agilent) the HPLC bottle (6ml) of glass system. By capsule cap being placed on capsule body and light pressure with by glueBe encapsulated and close. Capsule is kept under 40 DEG C/75%RH at (vial is opened) or 50 DEG C (vial sealing). As mentioned above,Measure the amount of bendamustine hydrochloride and related substances with HPLC. Result is shown in table 15:
It is evident that, although described capsule preparations is prepared from by pure hydrochloric acid bendamustine, without any enter oneThe procedure of processing of step, but compared with tablet formulation of the present invention, the stability of described capsule preparations is very different. 40 DEG C/75%Under RH (vial is opened) and at 50 DEG C (vial sealing) preserve within one month and all can form more degradedProduct. 40 DEG C, 75%RH(relative humidity) and after bottle preserves one month open in the situation that, the amount of hydrolysate HP1 increasesAdd 4 times. Concerning the bottle of sealing, the content of HP1 is even higher, and perhaps this be owing to having occurred to react with capsule. In a word, withCapsule is compared, and tablet provides stablizes to obtain many solid dosage forms.
Embodiment 14
8.0g hydroxypropyl methylcellulose and 1.5gPEG6000 are dissolved in to 88.5g pure water. Afterwards by 2.0g yellow threeBeing oxidized two iron and 0.5g titanium oxide is scattered in wherein to generate coating solution. Use film coating machine taking with respect to every tablet quality as 3%The amount of described solution by gained tablet coating in embodiment 11.
Embodiment 15
The preparation method of 1000 tablets of tablets
All pack all label compositions except cataloid and stearic acid into Somakon container (5L). AddBendamustine also mixes 4 minutes (wiper (wiper) 10rpm) with 1000rpm. By 0.5mm screen cloth, gained is mixedCompound sieves. Mixture is reloaded to described container, and add cataloid. Mix under these conditions 2Minute. Add afterwards stearic acid and continue and mix 1 minute. By 0.5mm screen cloth, mixture is sieved subsequently, reload instituteState container and mix 30 seconds again, mixing condition is all identical with above-mentioned condition.
Be the circular tablet with following characteristics by described mixture compression forming:
Average diameter: 9.5mm; Average quality: 254.6mg(is initial) final to 257.2mg(); Friability 0.1%; On averageHardness: 122N(is initial) final to 128N().
Adopt afterwardsDispersion is carried out film coating until mass penalty 5% to described tablet.
The average quality of film coating tablet is 268.4mg.
In the amber glass bottle of sealing, under 40 DEG C/75%RH, preserve label and film coating tablet. As above instituteState, measure the amount of bendamustine hydrochloride and the related substances such as catabolite, synthetic accessory substance with HPLC. ResultShown in table 16b.1 and table 16b.2.
*3: for main peak, the not clear compound peaks under 0.69 relative retention time
Embodiment 16
The preparation method of 1000 tablets of tablets
All pack all label compositions except cataloid and stearic acid into Somakon container (5L). AddBendamustine also mixes 4 minutes (wiper 10rpm) with 1000rpm. By 0.5mm screen cloth by gained mixture mistakeSieve. Mixture is reloaded to described container, and add cataloid. Mix under these conditions 2 minutes. Add afterwardsStearic acid and continuation mix 1 minute. By 0.5mm screen cloth, mixture is sieved subsequently, reload described container and againMix 30 seconds, mixing condition is all identical with above-mentioned condition.
Be the circular tablet with following characteristics by described mixture compression forming:
Average diameter: 9.5mm; Average quality: 262.4mg(is initial) final to 254.4mg(); Friability: 0.1%(risesBegin) final to 0.2%(); Average hardness: 98N(is initial) final to 91N().
Adopt afterwardsDispersion is carried out film coating until mass penalty 3% to described tablet.
The average quality of film coating tablet is 273.5mg.
In the amber glass bottle of sealing, under 40 DEG C/75%RH, preserve label and film coating tablet. As above instituteState, measure the content of bendamustine hydrochloride and related substances with HPLC. Result is shown in table 17b.1 and table 17b.2:
Embodiment 17
The preparation method of 1000 tablets of tablets
All pack all label compositions except cataloid and stearic acid into Somakon container (2.5L). AddEnter bendamustine and mix 4 minutes (wiper 10rpm) with 1000rpm. By 0.5mm screen cloth by gained mixture mistakeSieve. Mixture is reloaded to described container, and add cataloid. Mix under these conditions 2 minutes. AfterwardsAdd stearic acid and continue and mix 1 minute. By 0.5mm screen cloth, mixture is sieved subsequently, reload described container alsoAnd mix 30 seconds, mixing condition is all identical with above-mentioned condition again.
Be the circular tablet with following characteristics by described mixture compression forming:
Average diameter: 9.5mm; Average quality: 252.2mg(is initial) final to 250.7mg(); Friability: 0.1%(risesBegin) final to 0.2%(); Average hardness: 65N(is initial) final to 73N().
Adopt afterwardsDispersion is carried out film coating until mass penalty 3% to described tablet.
The average quality of film coating tablet is 253.6mg.
In the amber glass bottle of sealing, under 40 DEG C/75%RH, preserve label and film coating tablet. As above instituteState, measure the amount of bendamustine hydrochloride and related substances with HPLC. Result is shown in table 18b.1 and table 18b.2:
Embodiment 18
The preparation method of the preparation PF1 of 600 tablets of tablets:
Weigh 33.06g bendamustine, 111.60g dextrose, 40.92g lactose, 11.22g microcrystalline cellulose and 1.20gDolomol being transferred in double-layer polyethylene bag mixes 5 minutes. Afterwards described mixture of powders is transferred to centering type compressing tabletIn the hopper of machine (KorschEK0), it is the circular tablet with following characteristics by its compression forming: average diameter: 10.0mm;Average quality: 336.9mg(is initial) final to 335.98(); Friability: 0.15%; Average hardness value: 69.25N(is initial) extremely68.60N(final).
Afterwards in coating pan (4M8ForMatePanCoat), with 9% white Opadry (TMWhite) waterProperty suspension is label dressing, and is dried. The average quality of described tablet is 342.42mg. Afterwards described tablet is packed intoIn amber glass bottle with vice sealing, and be kept under 40 DEG C/75%RH.
The preparation method of the preparation PF2 of 600 tablets of tablets:
Weigh 33.06g bendamustine, 111.42g lactose, 39.60g trehalose, 12.60g crosslinked polyethylene pyrrolidinesKetone and 1.32g dolomol being transferred in double-layer polyethylene bag mixes 5 minutes. Afterwards described mixture of powders is transferred to partiallyIn the hopper of core type tablet press machine (KorschEK0), be the circular tablet with following characteristics by its compression forming: average diameter:10.0mm; Average quality: 332.95mg(is initial) final to 332.12(); Friability: 0.3%; Average hardness value: 65.9N(risesBegin) final to 59.0N().
Afterwards in coating pan (4M8ForMatePanCoat), with 9%TMWhite waterborne suspension is by sheetCore dressing, and be dried. The average quality of described tablet is 340.1mg. Afterwards described tablet is packed into vice and sealedAmber glass bottle in, and be kept under 40 DEG C/75%RH.
The preparation method of preparation PF3:
Weigh sorbierite and anhydrous dextrose. 140.64g sorbierite is dissolved in 105.48g pure water, uses subsequently instituteSolution in fluidized bed pelletizer (4M8ForMateFluidBed) by the granulation of 659.36g dextrose. Afterwards, at 60 DEG CDried particles, and sieve by 850 μ m screen clothes.
Weigh 33.06g bendamustine hydrochloride, 149.82g sorbierite/dextrose particle, 13.8g microcrystalline cellulose and1.32g dolomol, and be transferred in double-layer polyethylene bag and mix 5 minutes. Afterwards described mixture of powders is transferred to biasIn the hopper of formula tablet press machine (KorschEK0), be the circular tablet with 10.0mm average diameter by its compression forming. This sheetThe average quality of agent is that 335.99mg(is initial) final to 339.50(); Friability is 0%; Average hardness value is that 125.60N(risesBegin) final to 129.7N(). Make afterwards the preprocessing process of following two steps of described tablet experience (only selected batch be enteredOK): described tablet is placed under 25 DEG C/60%R.H. two hours, is placed in afterwards at 40 DEG C two hours.
Afterwards in coating pan (4M8ForMatePanCoat), with 9%TMWhite waterborne suspension is by instituteState tablet coating. The average quality of described tablet is 341.43mg. Afterwards described tablet is packed into the amber with vice sealingIn look vial, and be kept under 40 DEG C/75%RH.
As mentioned above, measure in the film coating tablet of preserving bendamustine hydrochloride and related substances with HPLCAmount. Result is shown in table 19b.1 to 19b.3:
3. dissolution test
Embodiment 19
When T=0, in simulated gastric fluid, the tablet formulation of embodiment 11 and 12 is carried out to dissolution test. Stripping sample is carried outTest is to analyze (pillar: ZorbaxBonus-RP, 5 μ m by HPLC; Column oven temperature: 30 DEG C; Automatic sampler temperatureDegree: 5 DEG C; Detector: 254nm). Prepare simulated gastric fluid (pH value 1.5) by following steps: 2g sodium chloride p.A. is dissolved inIn 1000ml water, and pH is adjusted to 1.5 ± 0.05 with 5N hydrochloric acid. According to European Pharmacopoeia 6.0 2.9.3 chapters, use device 2(oar formula device) carries out dissolution test. Paddle board rotating speed is 50rpm, and temperature is 37 DEG C ± 0.5 DEG C, and the amount of dissolution medium is 500ml.
Embodiment 11(tablet formulation 1) and embodiment 12(tablet formulation 2) tablet formulation result in following table 20a, showGo out:
Table 20a:
When T=0, the identical stripping examination that the coated tablet preparation of embodiment 15, embodiment 16 and embodiment 17 is carried outThe result of testing is shown in following table 20b:
Table 20b
The corresponding stripping data of the tablet of embodiment 18 are:
Can be learnt by foregoing, all tablet formulations of the present invention all demonstrate the behavior of bendamustine Fast Stripping.Particularly, preparation of the present invention demonstrates as bendamustine stripping behavior defined previously herein.
4. in vivo studies
In beasle dog, carry out the animal organism availability research of bendamustine: PK outline
Research experiment 1
Research purpose is to determine (4 kinds of oral formulations altogether) 1 in 3 tablet formulations (T1-3) and in 1 capsules preparation (C)The bioavilability of dosage (being 50mg) bendamustine: AUC and Cmax
The total quantity of required animal: 16
Basic Design:
Cross-over design, 8 animals of each branch (arm):
Table 21a:1 phase (tablet of single dose or capsule, the 1st day):
One week wash-out (wash-out)
The table 21b:2 phase (one week afterwards 1 phase, following every kind of preparation of single dose, the 8th day):
One week wash-out
The table 21c:3 phase (one week afterwards 2 phases, following every kind of preparation of single dose, the 15th day):
Research experiment 2
Research purpose is to determine (3 kinds of oral formulations altogether) 1 dosage in 1 tablet formulation T4 and in 1 capsules preparation (C)The bioavilability of (being 50mg) bendamustine: AUC and Cmax
The total quantity of required animal: 16
Basic Design:
Cross-over design, 8 animals of each branch:
Table 22a:1 phase (capsule of single dose, the 1st day)
One week wash-out
The table 22b:2 phase (one week afterwards 1 phase, following every kind of preparation of single dose, the 8th day):
Embodiment 20
The coated tablet of the embodiment 18 that male and female dog oral administration is comprised to 50mg bendamustine (use by preparation 3Dressing, tablet T4), and compare with the capsule of reference example.
The mean plasma concentration of the coated tablet of capsule preparations and embodiment 18 relation is in time shown in Fig. 3.
Embodiment 21
The coated tablet of the embodiment 15,16 or 17 that male and female dog oral administration is comprised to 50mg bendamustine(tablet T1 to T3), and compare with the capsule of reference example.
The relation of the average blood plasma-time of the coated tablet of capsule preparations and embodiment 15-17 is shown in Fig. 3.
In order to test following aspect:
-evaluate which kind of sugar or sugar mixture and be suitable for obtaining and there is Fast Stripping behavior and hardness number to be suitable for the chemistry of dressing steadyFixed tablet;
Compatibility between-evaluation API and excipient;
-by studying that following different preparation technology researches and develops placebo batch and containing API batch, described preparation technologyFor: non-slurry pelletizing, direct pressing and wet granulation;
-evaluate the weight ratio of different bendamustine hydrochloride/sugar;
-evaluate sugared purity on bendamustine hydrochloride impurity form impact;
-research the technical performance of moisture on prepared tablet and the impact of stability;
-use the bendamustine hydrochloride product of commercially available freeze-dryingPrepare tablet, and by thisThe character of the prepared tablet of the sweet mellow wine of the character of a little tablets and use a great deal of and bendamustine hydrochloride is compared.
Use following sugar to prepare tablet of the present invention, this tablet comprises 50mg bendamustine and (reaches not for hydrochloric acid benzeneDepartment spit of fland is 55mg).
Table 23
By observing physical appearance, qualification test (HPLC), dissolution test, content and related substances analysis (HPLC), containingAmount uniformity test (HPLC), hardness test and water content (KarlFischer method) are evaluated the quality of prepared batch. WillBatch pack amber glass bottle into, under the preservation condition describing in detail in following table, carry out acceleration for stabilization Journal of Sex Research. Made to every kindStandby containing API batch, some tablet is kept at 5 DEG C, using as backup sample.
Next, the various excipient relevant to tablet manufacture are studied. By using these excipient, adoptCarry out some placebo preparations with non-slurry pelletizing and test, thereby obtain about the preparation that is applicable to obtaining the tablet with good qualityThe preliminary information of method.
Use the disintegrant of two types: as the microcrystalline cellulose of standard disintegrant (PH112), and only useIn the PVPP of batch D001T/002For a batch D001T/002(filler:Lactis Anhydrous) selectIt is the similitude based between said preparation and embodiment 9 prototype formulations. For instituteThere is prepared batch, use dolomol as lubricant. For the non-slurry pelletizing preparation process of placebo test comprise withLower step:
1. lubricant (83.3% of the total amount of accurate weighing sugar and part amountw/w), in Polythene Bag, mix afterwards 2 pointsClock.
2. use the tablet press machine that is equipped with 18mm diameter drift by gained mixture compacted.
3. use 850 microns of screen clothes that gained blank (slug) is sieved.
4. weigh particle and in Polythene Bag by the lubricant (16.7% of itself and disintegrant and surplusw/w) mix 2 pointsClock, carries out compressing tablet with the drift of 10mm diameter afterwards.
The analysis that table 24 and table 25 have been summed up the composition of every kind of placebo preparation and final mixture and tablet are carried outThe result of test. In table 16, illustrate in the analysis and characterization process in the preparation process of placebo batch and/or at themThe result that row is observed.
Placebo batch D001T/001, D001T/002, D001T/004, D001T/013, D001T/015 are carried outAnalyze and the physical results demonstration, these preparations are suitable for being prepared and by adding API to carry out by non-slurry pelletizingFurther research. Other all preparations are characterised in that powder is difficult to compacting, and in the situation that having obtained tablet tabletFriability is high.
Batch D001T/005(filler: β – cyclodextrin) demonstrate good behavior in dry process process, high hardDegree, low friability, but long disintegration time. By using superdisintegrantAnd add API to come thisPlant preparation and further study (seeing content below).
With bendamustine hydrochloride/sugar weight ratio of 1:5, adopt non-slurry pelletizing prepared batch
To be assessed as the placebo system that is more suitable for preparing by non-slurry pelletizing the tablet that comprises active pharmaceutical ingredient (API)Agent changes to and comprises API, and has inquired into two kinds of API/ sugar weight ratios: 1:5 and 1:2.
In this section, be that the preparation of the API/ sugar of 1:5 describes to containing weight ratio.
Use the disintegrant of two types: as the microcrystalline cellulose of standard disintegrant (, and only right PH112)The PVPP that batch D001T/022 usesFor all prepared batch,Use dolomol as lubricant.
Adopt non-slurry pelletizing preparation to comprise the following steps containing the process of API batch:
1. lubricant (83.3% of the total amount of accurate weighing sugar, part amountw/w) and bendamustine hydrochloride, afterwards at bilayerIn Polythene Bag, mix 5 minutes.
2. use the tablet press machine pressed powder mixture that is equipped with 18mm diameter drift.
3. use 850 microns of screen clothes that gained blank is sieved, to obtain particle.
4. weigh particle and by the lubricant (16.7% of itself and disintegrant and surplusw/w) in double-layer polyethylene bag, mix5 minutes.
5. use 10mm diameter drift by gained mixture compressing tablet.
Table 27 has been summed up every kind of prepared composition containing API preparation, and the final mixture that comprises API is dividedAnalyse the result of test; Table 28 has been summed up the result of resulting product being carried out to analytical test.
The weight ratio of table 27. non-slurry pelletizing-API/ sugar is 1:5. Containing composition and the analysis knot of the final mixture of API batchReally.
The weight ratio of table 28. non-slurry pelletizing-API/ sugar is 1:5. Containing the analysis result of the tablet of API batch.
The result (being mainly content uniformity and purity) of final mixture and resulting product being carried out to analytical test is greatlyAll in most cases good. All containing API batch all show gratifying quality uniformity, API content uniformity andLow impurity content. The impurity situation of all preparations all meets API specification (in the specification limits in Table), therefore in preparation processDo not degrade.
Two kinds containing API batch API analyze in all show low value, can by this result owing to little batch scale withAnd loss in preparation process and final mixture is carried out to IPC sample used.
With the API/ sugar weight ratio of 1:2, prepared by employing non-slurry pelletizing contains API batch
With the ratio of 1:2 again to adopting before non-slurry pelletizing to prepare that API/ sugar-tablet agent that weight ratio is 1:5 studiedAll carbohydrates are evaluated.
Preparation process is described above. In this case, with 8mm diameter drift, gained mixture is carried out to compressing tablet.
Use the disintegrant of two types: as the microcrystalline cellulose of standard disintegrant (, and only right PH112)The PVPP that batch D001T/105 usesFor this batch, we are rightPH112 andUse inquire into. According to logical under the ratio of the API/ of 1:5 sugar beforeCrossing the prepared Beta-cyclodextrin-based preparation of non-slurry pelletizing (result before seeing) selects
Every kind that under the weight ratio of the API/ sugar that table 29 and table 30 have been summed up at 1:2, prepares by non-slurry pelletizing containing APIThe composition of preparation, and the result that final mixture and tablet are carried out to analytical test. Allly all demonstrate and closed containing API batchSuitable quality uniformity, API content uniformity and low impurity content. In most of the cases, friability and hardness number meetSpecification. In the situation of a batch D001T/093, D001T/095 and D001T/096,6 tablets are carried out to the result of dissolution testDemonstrate outside specification value, have high RSD, described test expands to the sample of 12 tablets.
Two kinds of disintegrants (PH112 and) descend Beta-cyclodextrin-based tablet all to demonstrate wellCharacter.
The weight ratio of table 29. non-slurry pelletizing-API/ sugar is 1:2. Containing composition and the analysis knot of the final mixture of API batchReally.
With the API/ sugar weight ratio of 1:5, what employing direct tablet compressing was prepared contains API batch.
To have be suitable for by non-slurry pelletizing prepare this feature carbohydrate adopt direct tablet compressing study, developThere is the tablet of the API/ sugar ratio of 1:5.
Use the disintegrant of two types: as the microcrystalline cellulose of standard disintegrant (, and only right PH112)The PVPP that batch D001T/029 uses
This preparation process comprises the following steps:
1. weigh API and excipient.
2. described raw material be transferred in double-layer polyethylene bag and mix approximately 5 minutes, until obtain the Powdered mixed of homogeneousCompound.
3. described powder mixture is transferred in tablet press machine hopper.
4. use the centering type tablet press machine that is equipped with 10mm diameter drift by described powder mixture compression forming.
Prepared by employing direct tablet compressing contains the feature of API batch shown in following table.
The weight ratio of table 31. direct tablet compressing-API/ sugar is 1:5. Containing composition and the analysis knot of the final mixture of API batchReally.
Analytical test acquired results is listed in table 32.
The weight ratio of table 32. direct tablet compressing-API/ sugar is 1:5. Containing the analysis result of the tablet of API batch.
As above shown in table, except a batch D001T/030(filler: sucrose 97%+ maltodextrin 3%) demonstrate non-Beyond the friability value of the API content of homogeneous and increase slightly, the described tablet that comprises API of preparing by direct tablet compressing is equalThe difference of any key of tablet not demonstrating and prepare by non-slurry pelletizing.
Wet granulation:
The test of the placebo property inquired into
According to the result of described scheme Part I and Part II gained, those are not suitable for non-slurry pelletizing or are directly pressedThe carbohydrate of sheet carries out wet granulation research.
The scheme of research wet granulation technology illustrates hereinafter.
According to the step described in Fig. 4 flow chart, every kind of sugar is carried out to granulation. Last in every step, by moistening particleChange sugar dry, and carry out compression forming test and whether be suitable for compressing tablet to evaluate particle. Only suspicious to compression forming result of the testGranulating sugar prepare placebo batch. The composition of placebo test and correlation analysis result are shown in table 33.
Prepare placebo batch according to following steps:
1. use fluid bed or high shear granulator, adopt water or sorbitol solution to carry out wet granulation to described sugar(seeing flow chart and the table 23 of above-mentioned wet granulation preparation test).
2. dry moistening granulating sugar in fluidized bed pelletizer or in baking oven.
3. by the screen cloth that uses 850 microns and 710 microns, described granulating sugar is sieved.
4. weigh all the components of corresponding preparations and in Polythene Bag, mix 2 minutes.
5. use the centering type tablet press machine that is equipped with 10mm diameter drift by described powder mixture compression forming.
For all prepared batch, use respectively AvicelPH112 and dolomol as disintegrant and lubricatedAgent.
With the API/ sugar weight ratio of 1:5, what employing wet granulation was prepared contains API batch
All that is shown to the carbohydrate that is not suitable for preparing by non-slurry pelletizing or direct tablet compressing technology tablet to carry outPreparation test including wet granulation process.
The preparation process of these tests of carrying out with laboratory scale is summarized as follows:
1. use fluid bed or high shear granulator, adopt water or sorbitol solution to carry out wet granulation to described sugar(seeing flow chart and the table 34 of above-mentioned wet granulation preparation test).
2. dry moistening granulating sugar in fluidized bed pelletizer or in baking oven.
3. sieve by the screen cloth of 850 microns and 710 microns.
4. weigh API and excipient and in double-layer polyethylene bag, mix 5 minutes.
5. use the centering type tablet press machine that is equipped with 10mm diameter drift by described powder mixture compression forming.
For all prepared batch, use respectively AvicelPH112 and dolomol as disintegrant and lubricatedAgent.
Table 33 and table 34 are listed every kind of composition containing API preparation of preparing by wet granulation, and to final mixtureThe result of carrying out analytical test with tablet
In most of the cases, all up to specification to the result of final mixture and analytical test that finished product carries out. In systemIn standby process, do not degrade.
In studied sugar, only have fructose MS(Galam) be not suitable for adopting wet granulation to process: containing API batchThe friability of D001T/047 is high, and a batch D001T/082 demonstrates, and friability and hardness number exceed specification.
Batch D001T/060, D001T/061, D001T/082 and D001T/086 have low value in API analyzes, and rightIn batch D001T/082 and D001T/086, although used 850 microns and 710 microns of screen clothes to carry out mistake to particleSieve, but still do not meet content uniformity. This possibility of result is mixed to get bad owing to powder.
With the API/ sugar weight ratio of 1:2, what employing wet granulation was prepared contains API batch
With the ratio of 1:2 again to adopting before wet granulation to prepare that API/ sugar-tablet agent that weight ratio is 1:5 studiedAll carbohydrates are evaluated.
Under the ratio of 1:2, fructose is not evaluated, because gained particle is unsuitable for compressing tablet.
For all prepared batch, use respectively AvicelPH112 and dolomol as disintegrant and lubricatedAgent.
In order to improve the uniformity of API content, adopt following steps prepare these containing API batch:
1. the program of optimizing before using is carried out wet granulation to described sugar.
2. preparation is containing the mixture of API.
3. pair described mixture carries out non-slurry pelletizing (blank preparation → blank sieves).
4. with 8mm diameter drift, gained mixture is carried out to compressing tablet.
Step 3(carries out non-slurry pelletizing to described mixture) see above.
Table 36 and table 37 illustrate by adopting the sugar of wet granulation, the API/ of 1:2 sugar weight than under prepared containing APIBatch composition and analysis result. In most of the cases, friability exceeds specification. The changes in weight of API/ sugar to batchD001T/084(filler: granulating sweet mellow wine) technical performance be safe from harm.
The impact of API/ sweet mellow wine weight ratio
Preparation mannitol based tablet, with study the ratio of following API/ sweet mellow wine: 1:0.01,1:0.1,1:0.5,1:1.7,1:4,1:5,1:6 and 1:10. Above the preparation (standard preparation) of the API/ sweet mellow wine weight ratio with 1:5 is reportedRoad.
For the preparation of these batches, respectively AvicelPH112 and dolomol are used as to disintegrant and lubricant. CloseIn preparation process, for the ratio of 1:1.7,1:4 and 1:6, accurate weighing wet granulation sweet mellow wine, bendamustine hydrochloride andExcipient, and they are mixed 5 minutes in double-layer polyethylene bag. For the ratio of batch D001T/110(1:10), carry out pre-Mix. In this case, bendamustine hydrochloride is mixed 5 minutes with the excipient mixture of half amount. Afterwards, by gainedMixture joins in the excipient of surplus, and mixes 5 minutes again. Use be equipped with suitable drift (to 1:1,1:1.7 andThe ratio of 1:2 is used 8mm drift, and the ratio of 1:4 and 1:6 is used to 10mm drift, and the ratio of 1:7 is used to 12mm drift, andThe ratio of 1:10 is used to 14mm drift) tablet press machine by final mixture compressing tablet.
For the ratio of 1:0.01,1:0.1 and 1:0.5, we have adopted the preparation process of above-mentioned report (sugar to be wetCarry out non-slurry pelletizing after method granulation) improve API content uniformity. Use 6mm diameter drift by gained mixture compressing tablet.
Following table (table 38 and table 39) summed up prepared by impact for studying different API/ sweet mellow wine ratios containing API preparationComposition and analysis result. Batch D001T/111, D001T/083 and D001T/106 demonstrate high friability, and for batchInferior D001T/106, D001T/108 and D001T/109, do not meet content uniformity, and before having departed from, the data of gained becomeGesture. This possibility of result is owing to such fact, and these batches are much may have the new of different physical properties by usingBendamustine hydrochloride (article No.: F08-05873) and preparation.
Carbohydrate combination research
Table 40 and table 41 show the result about carbohydrate combination research.
Following combination is studied:
-monose/disaccharides 1:1
（*) sweet mellow wine (Pearlitol200SD)/Lactis Anhydrous (SuperTab21AN)
Sorbierite (NeosorbP60W)/maltose (SunmaltS)
-compound sugar/monose 1:1
（*) D-melezitose monohydrate/(*) anhydrous dextrose ST0.5
（*) granular five water gossyposes/(*) granular sweet mellow wine (Pearlitol200SD)
-compound sugar/disaccharides 1:1
（*) granular five water gossypose/lactose monohydrates (Supertab14SD)
Beta-schardinger dextrin-(KleptoseDC)/sucrose (EVSaccharide)
（*) by wet granulation by these sugared granulations.
Preparation process comprises crude or carry out direct tablet compressing through granular sugar.
Respectively AvicelPH112 and dolomol are used as to disintegrant and lubricant, carry out following steps and prepare these batchesInferior:
1. the sugar described in accurate weighing (or granular sugar), bendamustine hydrochloride and excipient, and by them twoIn layers of polyethylene bag, mix 5 minutes.
2. use 10mm diameter drift by gained mixture compressing tablet.
Table 40. carbohydrate combination research. Containing composition and the analysis result of the final mixture of API batch.
For combining the tablet of preparing, research carbohydrate demonstrates generally good character. But, batch D001T/102(five water gossypose/sweet mellow wine (Pearlitol200SD)) demonstrates high friability, and batch D001T/100 and D001T/049 API content heterogeneity.
Embodiment 22. freeze-drying bendamustine hydrochlorides (Ribomustin) and bendamustine hydrochloride/sweet mellow wine tablet (weight ratio of API/ sugar is 1:1.2)
Use by commercially available intravenous administration goodsThe lyophilized products obtaining, or use wet granulation sweet dewAlcohol and bendamustine hydrochloride are prepared and are contained the tablet that weight ratio is bendamustine hydrochloride/sweet mellow wine of 1:1.2.
Be prepared according to following experimental implementation: by freeze-dried powder certainlyIn bottle, take out and useThe net of 850 microns sieves. Accurate weighing gained powder and lubricant (dolomol) also mix them 5 points in Polythene BagClock. The compacting that this mixture is slowly transferred to tablet press machine is indoor, and uses 8mm diameter drift manually to suppress to obtain little baseMaterial. Use the net of 850 microns that this blank is sieved, and the particle that uses the manual obsession of 8mm diameter drift to obtain.
Adopt and prepare bendamustine hydrochloride/sweet mellow wine tablet with above-mentioned same operation sequence in this example.
The composition of described preparation is shown in table 42.
Table 42.Ribomustin and bendamustine/sweet mellow wine tablet. Containing the composition of the final mixture of API batch.
(*) be equivalent to 45.16% bendamustine hydrochloride and 54.20% sweet mellow wine
Table 43 illustrates the tablet and the non-freeze-drying hydrochloric acid of use that use freeze-drying bendamustine hydrochloride/mannitol mixture gainedThe data that the tablet of bendamustine/mannitol mixture gained is compared.
Table 43.Ribomustin and bendamustine/sweet mellow wine tablet. Containing the analysis result of the tablet of API batch
Using the impurity situation of bendamustine hydrochloride API as with reference to index (in specification limits in Table), batch D001T/125 demonstrate impurity HP1 exceeds specification value. Dissolution test result is outstanding to be shown, although contain freeze-drying bendamustine hydrochloride/sweetThe stripping behavior of the tablet of dew alcohol mixture is very fast after 10 minutes, but after 30 minutes, the stripping behavior of two kinds of preparationsAll meet existing specification. The friability of batch D001T/126 exceeds specification, and owing to lacking the material of q.s, does not therefore haveA batch D001T/125 is tested.
Embodiment 23: the absolute bioavailability of oral bendamustine to cancer patient
Arrange 12 patients altogether to carry out the random bidirectional crossed research of 1 open mark of phase, to study in oral administrationThe bioavilability of bendamustine after the liquid filled hard capsules preparation of bendamustine hydrochloride. Recruiting 14 suffers from multipleProperty myeloma, B-cellular type chronic lymphocytic leukemia or late period inertia NHL patient, and utilize benzene to reachMo Siting treats it. By intravenous administration bendamustine, these patients are treated in advance, but should be firstBefore inferior study drug-administration at least seven angels they accept last intravenous injection cycle (lastintravenousCycle). At signature Informed Consent Form and after screening (the-21 days to the-2 days), qualified patient is provided and respectively facedPatient's numbering that bed center is special. Patient is random one of the following dosage regimen of accepting at the 1st day, accepts another afterwards at the 8th dayPlant dosage regimen:
-110.2mg(2 × 55.1mg) bendamustine hydrochloride list oral dose
-110mg bendamustine hydrochloride list vein dosage
(will be used for system with the form of a) oral capsule (LFHC preparation (liquid filling hard-shell capsule)) with b) through intravenous solutionAfter the powder restructuring of standby parenteral solution, obtain) form bendamustine is provided. Utilize 55.1mg bendamustine hydrochloride, 1.2mgMethyl hydroxybenzoate, 0.12mg Nipasol, the top hydroxy-methylbenzene of 0.12mg, 10.9mg ethanol and 532.56mgRH40 prepares LFHC preparation (each capsule). The bottle that powder is housed for concentrate solution is German commercially available prodEvery bottle contains 100mg bendamustine hydrochloride and the sweet mellow wine as excipient. Say according to medicineThe instruction of bright book, by this product and water for injection restructuring, making the final concentration of bendamustine hydrochloride is 2.5mg/ml, and entersOne step utilizes 0.9%NaCl to dilute, until be about 500ml before patient is used.
Make patient enter clinical center and carry out the research of 2 phases: the-1 day to the 2nd day (1 phase) and the 7th day were to the 9th day (2Phase). Having 12 patients receives treatment at random. 6 patients accept such treatment: 110.2mg(2 × 55.1mg) single oral agentsAmount bendamustine hydrochloride (the 1st day), the mono-vein dosage of 100mg bendamustine hydrochloride (the 8th day) afterwards; And other 6 troublePerson accepts to exchange the treatment of said sequence. Between two treatments, make the patient experience wash-out phase of at least 7 days.
Bendamustine is metabolised to nonactive metabolin monohydroxy bendamustine (HP1) and dihydroxy benzenes by hydrolysisBendamustine (HP2), and be metabolised to active metabolite gamma-hydroxy bendamustine by Cytochrome P450 (CYP1A2)And N-demethyl bendamustine (M4) (M3).
At the 1st day and the 8th day, after per os and intravenous administration bendamustine, detect benzene in plasma sample and urine sampleThe concentration of bendamustine and bendamustine active metabolite (M3 and M4). After completing for the second treatment phase or put in early daysAfter return/withdrawal, make patient return to clinical center and carry out the research of 7 to 14 days and finish to follow up a case by regular visits to (end-of-studyVisit). Afterwards, calculate the pharmacokinetic parameter of bendamustine and metabolin thereof.
Do not arrange or carry out interim analysis.
Obtain following result:
Crowd:
In 23 patients for this research screening, random arrangement 14 patients treat, and makes them accept at least 1 doseThe drugs of amount. This comprises: 6 patients accept per os/accept through vein/per os through treatment and 8 patients of vein orderThe treatment of order. In these 14 patients:
-1 because violate the agreement (drug combination) also only accepted oral drugs and therefore arranged through vein dispenserRemove;
Because not meeting the requirement of Evaluation On The Bioavailability, vomiting got rid of from oral analysis for-1;
-1 due to adverse events (adverseevent) by from getting rid of through vein dispenser. This patient has only acceptedOral administration and not accepting through intravenously administrable.
In 14 patients, having 10 (71%) is the male sex, and is all white man. Patient age scope is 54 to 82 years old, averageAbout 70 years old. In these patients, there are 7 and suffer from Huppert's disease, suffer from inertia NHL for 4, have 3 to suffer fromChronic lymphocytic leukemia.
Pharmacokinetics result:
The drug plasma kinetic parameter of bendamustine (alkali), M3 and M4 is shown respectively in table 44, table 45 and table 46.According to statistical analysis, the absolute bioavailability of bendamustine (oral AUCinfWith vein AUCinfRatio) be how much of 66%(Average: 90%, CI:55%, 78%). C after oral administrationmaxFor C after intravenously administrablemax42%(90%CI:32%,54%）。
Table 44: the drug plasma kinetic parameter of bendamustine
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
Arithmetic mean of instantaneous value. Geometrical mean is 66%(90%CI:55%, 78%).
C after oral administrationmaxFor C after intravenously administrablemax42%(90%CI:32%, 54%).
The drug plasma kinetic parameter of table 45:M3
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
The drug plasma kinetic parameter of table 46:M4
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
After oral administration, the absorption t of bendamustinemaxFor approximately 0.95 hour, individual value at 15 minutes to 1.8Between hour. After intravenous administration, average CL is 21.2L/h. In oral administration use with after intravenous administration, average t1/2Be approximately 30 minutes. After intravenous administration, VZAnd VSSBe respectively 14.7L and 10.3L.
The plasma exposure amount of M3 and M4 is significantly lower than bendamustine. After oral administration, bendamustine averageAUCinfHigher 10.6 times and 88 times than M3 and M4 respectively. Compared with bendamustine, for oral administration and through intravenous administration andSpeech, the AUC of M3infThe AUC of value and M4infValue is all similar. According to statistical analysis, the AUC of M3 after oral administrationinfForAUC after intravenous administrationinf86%(90%CI:76%, 98%). In the situation of M4, be 88%(90%CI:77%, 102%).
The urine medication kinetic parameter of bendamustine, M3 and M4 is shown respectively in table 47,48 and 49. Constant urine(urineunchanged) percentage of dosage of discharging in is low (oral administration and be respectively 2.6% He through intravenous administration2.1%）。
Table 47: the urine medication kinetic parameter of bendamustine
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
The urine medication kinetic parameter of table 48:M3
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
The urine medication kinetic parameter of table 49:M4
Note:
Except 1 patient is due to vomiting AE, (pharmacokinetic analysis is established beyond insincere to cause its pharmacokinetic dataPut and change), all patients have accepted the drugs of at least 1 dosage, and have sufficient plasma concentration data, canDraw at least 1 pharmacokinetic parameter.
Safety results:
Per os and be all safe through intravenous administration bendamustine, and tolerance is good. In general, control at per osIn treatment, there is adverse events in 6 patients (43%) in treatment, and in vein treatment, 3 patients (25%) occur in treatmentAdverse events. The patient that 4 patients's (29%) that accept oral administration and 0 accept intravenously administrable occurred at least a kind studiedPerson thinks the adverse events relevant with drugs; These adverse events comprise: 1 patient's headache, 1 patient's headache and tiredLabor, 1 patient feels sick, 1 patient's vomiting. Except vomiting (order of severity is 2 grades), the order of severity of these events is 1Level.
The order of severity of most of adverse events is 1 grade or 2 grades. There are 3 grades of bad things in 1 patient who accepts oral administrationPart (serum creatinine increase, hypopotassaemia and acute renal failure) and 4 grades of adverse events (thrombopenia), researcher thinks thisAll relevant with patient's Huppert's disease, and irrelevant with drugs. Serum creatinine increases and acute renal failure is seriousAdverse events, causes patient to stop ahead of time this research. In research process, there is not death incident.
For hematology, biochemistry, urinalysis or vital signs parameter, in baseline or the definitely average change of changeIn change, do not observe the trend with clinical meaning. Small number of patients has abnormal hematology or biochemistry investigation result(being reported as adverse events); Researcher thinks that this is all irrelevant with drugs.
Aspect the rhythm of the heart, the mean change of baseline is little, and between treatment group, is similar. Due to patient in this researchHave different ages and case history, in screening and/or research, Most patients all has at least 1 " extremely, without clinical meaningJustice " electrocardiogram result. In screening and follow-up in vein and oral administration process, observe in vein/per os group1 patient there is abnormal, clinical conspicuousness atrial fibrillation, non-specific ST section is forced down and left axis deviation.
Conclusion:
Using capsule to carry out after single oral uses, the absolute bioavailability of bendamustine is how much of 66%(Mean value; 90%CI:55%, 78%).
After intravenous administration, average CL, the Vz of bendamustine and Vss be respectively 21.2L/h, 14.7L and10.3L。
After oral administration, bendamustine is rapidly absorbed (tmaxIntermediate value is about 0.95 hour). Average t1/2For about 30 minutes. After per os uses, about 2.6% dosage is excreted in constant urine, and in the situation of M3,Discharge 0.6%, in the situation of M4, discharge 0.1%. After oral administration, the exposed amount of M3 and M4 is respectively bendamustineApproximately 9% and 1%.
According to reported adverse events, clinical labororatory's evaluation, vital signs, physical examination and electrocardiogram, demonstrateAt most of suffer from inertia NHL, Huppert's disease or the white blood of B cellular type chronic lymphocytic above middle ageIn sick patient crowd, single oral dose (110.2mg) preparation of bendamustine and vein (100mg) preparation are safe,And tolerance is good.
Commercial Application
Pharmaceutical composition of the present invention demonstrates plurality of advantages. Patient can easily use this pharmaceutical composition and not needSupervise medical worker's help. Therefore may no longer need experience to be sent to the time-consuming process of hospital, comply with thereby improved patientFrom property.
Because described formulation is solid, therefore can swallow, this means that patient does not need to wait for to active component stripping.In addition,, because described formulation has good stability, therefore this formulation can easily at room temperature be preserved and not needAny special preservation condition.
By adopting formulation of the present invention, can significantly reduce the volume of described formulation. No matter from producing and processingAngle is still from the angle of patient compliance, and it is all favourable that size is dwindled.
Described pharmaceutical composition demonstrates high dissolution in vitro, and this can reduce bendamustine degraded in vivo, byBioavilability in the body of this improved bendamustine.

Claims (15)

1. a pharmaceutical composition for peroral dosage form, comprises: as bendamustine hydrochloride and the pharmaceutically acceptable figuration of active componentAgent, in the group forming below wherein said pharmaceutically acceptable excipient choosing freely:
-Cremophor RH40;
-polyoxyethylene-35-castor oil, or the combination of polyoxyethylene-35-castor oil and LABRASOL,The concentration of wherein said LABRASOL in described composition is 10% to 50%;
-ethylene oxide/propylene oxide block copolymerL44NF, orL44NF and colloid dioxyThe combination of SiClx, the concentration of wherein said cataloid in described composition is 2% to 8%, orThe combination of L44NF and LABRASOL, wherein said LABRASOL is in described combinationConcentration in thing is 10% to 45.4%;
Wherein when in the dissolution medium that the oar formula device that is 50rpm according to European Pharmacopoeia use rotating speed is 1.5 in 500ml, pH valueWhen measurement, described compositions display goes out such bendamustine stripping behavior: stripping at least 60% in 10 minutes, and at 20 pointsStripping at least 70% in clock, and stripping at least 80% in 30 minutes.
2. pharmaceutical composition according to claim 1, is characterized in that described pharmaceutical composition comprises 10mg to 1000mgDescribed active component.
3. according to the pharmaceutical composition described in any one in the claims, it is characterized in that described composition is installed in brightIn glue hard shell capsules.
4. treating following medical science disease for the preparation of per os according to the pharmaceutical composition described in any one in the claimsApplication in the medicine of shape, described medical science symptom is selected from: chronic lymphocytic leukemia, ALL, chronicGranulocytic leukemia, acute myeloblastic leukemia, Hodgkin's disease, NHL, Huppert's disease, breast cancer, ovumNest cancer, ED-SCLC and non-small cell lung cancer.
5. application claimed in claim 4, wherein said pharmaceutical composition and the activating agent combination that at least one is other are used, itsDescribed in the use of at least one other activating agent be before using described pharmaceutical composition, simultaneously or carry out afterwards, andAnd described other activating agent selects the group of free CD20 specific antibody, anthracycline derivatives, vinblastine or platinum derivatives composition.
6. application according to claim 5, is characterized in that: described CD20 specific antibody is Rituximab; DescribedAnthracycline derivatives is adriamycin or daunorubicin; Described vinblastine is vincristine, and described platinum derivatives be cis-platinum orCarboplatin.
7. according to the application described in any one in claim 4 to 6, described pharmaceutical composition and at least one corticosteroidBe used in combination, the use of wherein said corticosteroid be using before described pharmaceutical composition, simultaneously or carry out afterwards.
8. application according to claim 7, is characterized in that: described corticosteroid is prednisone or prednisolone.
9. according to the application described in any one in claim 4 to 6, wherein said active component is with per course for the treatment of of 50mg/m2/ everyPeople is to 1000mg/m2/ dosage between everyone is used.
10. according to the application described in any one in claim 4 to 6, wherein dosage regimen at least comprises:
-be 100mg/m at the 1st day and the 2nd day application dosage2/ everyone is to 600mg/m2/ everyone bendamustine,
-optionally, at the 1st day to the 5th day, be 50mg/m through vein or oral administration dosage2To 150mg/m2Cortex class solidAlcohol, and
-optionally use the other activating agent of suitable dosage, described activating agent selects free CD20 specific antibody, anthracene nucleus to deriveThe group of thing, vinblastine or platinum derivatives composition; And
After interval 2-4 week, described dosage regimen is repeated 4 to 15 times.
11. according to the application described in any one in claim 4 to 6, wherein uses with the dosage regimen that is selected from following schemeDescribed active component bendamustine:
-used 200-300mg at the 1st day and the 2nd day, the optional maintenance dose of using 50mg afterwards, once a day,
-from the 1st day to the 14th day, comprise the 14th day, use 50mg every day, or
-use 150mg, weekly, continue 3 weeks.
12. according to the application described in any one in claim 4 to 6, and wherein patient suffers from NHL, and instituteStating dosage regimen comprises: within the 1st day to the 5th day, use the active component bendamustine that total amount is 200mg/ people/sky, the 1st day warpIntravenous administration 2mg vincristine, and the 1st day to the 5th day, through intravenous administration 100mg/m2Prednisone, every three weeks repeat onceDescribed treatment, until described NHL is taken a turn for the better.
13. according to the application described in any one in claim 4 to 6, and wherein patient suffers from Huppert's disease, and described inDosage regimen comprises: the 1st day and the 2nd day amount of application are 100-250mg/m2The bendamustine hydrochloride of body surface area, and the 1stIt to the 4th day through vein or oral administration 60mg/m2Prednisone, every surrounding repeats once described treatment, until described multipleMyeloma is taken a turn for the better.
14. apply according to described in any one in claim 4 to 6, and wherein patient suffers from chronic lymphocytic leukemia, andDescribed dosage regimen comprises: the 1st day and the 2nd day amount of application are 100-200mg/m2The bendamustine hydrochloride of body surface area, andAnd the 1st day to the 4th day through vein or oral administration 60mg/m2Prednisone, every surrounding repeats once described treatment, until described inChronic lymphocytic leukemia is taken a turn for the better.
15. application according to claim 10, wherein patient suffers from follicular, inertia or lymphoma mantle cell, and instituteStating dosage regimen comprises: within the 1st day, application dosage is 375mg/m2Rituximab, and the 1st day and the 2nd day per os additionalUse 100mg/m2To 200mg/m2Bendamustine, every 28 days repeat once, until each described lymthoma is taken a turn for the better.
CN201180038034.4A 2010-06-02 2011-06-01 The peroral dosage form of bendamustine and therapeutical uses thereof Expired - Fee Related CN103037852B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP10005762 2010-06-02
EP10005762.9 2010-06-02
EP11075046 2011-03-14
EP11075046.0 2011-03-14
PCT/EP2011/002763 WO2011151086A1 (en) 2010-06-02 2011-06-01 Oral dosage forms of bendamustine and therapeutic use thereof

Publications (2)

Publication Number Publication Date
CN103037852A CN103037852A (en) 2013-04-10
CN103037852B true CN103037852B (en) 2016-06-15

Family

ID=44261747

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201180038034.4A Expired - Fee Related CN103037852B (en) 2010-06-02 2011-06-01 The peroral dosage form of bendamustine and therapeutical uses thereof

Country Status (25)

Country Link
US (2) US20130209558A1 (en)
EP (1) EP2575785B1 (en)
JP (2) JP2013527206A (en)
KR (1) KR101830147B1 (en)
CN (1) CN103037852B (en)
AR (1) AR081575A1 (en)
AU (1) AU2011260614B2 (en)
BR (1) BR112012030658B1 (en)
CA (1) CA2800277A1 (en)
CL (1) CL2012003340A1 (en)
CO (1) CO6640268A2 (en)
DK (1) DK2575785T3 (en)
EA (1) EA027786B1 (en)
ES (1) ES2935792T3 (en)
FI (1) FI2575785T3 (en)
IL (2) IL223309B (en)
JO (1) JO3659B1 (en)
MX (1) MX2012013873A (en)
MY (1) MY173881A (en)
NZ (1) NZ603874A (en)
PL (1) PL2575785T3 (en)
SG (1) SG185794A1 (en)
TW (1) TWI556819B (en)
WO (1) WO2011151086A1 (en)
ZA (1) ZA201208822B (en)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2911427T3 (en) * 2011-09-18 2022-05-19 Euro Celtique Sa Pharmaceutical composition comprising an HDAC inhibitor and a cyclopolysaccharide
AR092790A1 (en) 2012-02-01 2015-05-06 Euro Celtique Sa BENCIMIDAZOLIC DERIVATIVES OF HYDROXAMIC ACID
EP2641592A1 (en) 2012-03-23 2013-09-25 Salmon Pharma GmbH Pharmaceutical formulation comprising bendamustine
ES2535511T3 (en) 2012-04-26 2015-05-12 Helmut Schickaneder Esters of bendamustine and related compounds, and medical use thereof
CN104968335A (en) * 2013-01-07 2015-10-07 三亚制药(株) Novel fast-dissolving granule formulation having improved solubility
ES2957541T3 (en) * 2013-08-27 2024-01-22 Vasilios Voudouris Pharmaceutical compositions of bendamustine
GB201409485D0 (en) 2014-05-28 2014-07-09 Euro Celtique Sa Pharmaceutical composition
GB201409471D0 (en) 2014-05-28 2014-07-09 Euro Celtique Sa Pharmaceutical composition
GB201409488D0 (en) 2014-05-28 2014-07-09 Euro Celtique Sa Pharmaceutical composition
CN110772480B (en) * 2016-03-25 2022-05-17 南京百劲企业管理咨询有限公司 Bendamustine medicament composition and application thereof
AU2016426574B2 (en) 2016-10-11 2023-07-13 Euro-Celtique S.A. Hodgkin lymphoma therapy
GB201709403D0 (en) 2017-06-13 2017-07-26 Euro Celtique Sa Compounds for treating sarcoma
GB201709405D0 (en) 2017-06-13 2017-07-26 Euro Celtique Sa Compounds for treating ovarian cancer
GB201709406D0 (en) 2017-06-13 2017-07-26 Euro-Cletique S A Compounds for treating TNBC
GB201709402D0 (en) 2017-06-13 2017-07-26 Euro Celtique Sa Compounds for treating t-pll
CN112848583B (en) * 2020-12-31 2022-08-05 雅达环保科技(玉田)有限公司 Flame-retardant insulation board and preparation method thereof
WO2023113650A1 (en) * 2021-12-15 2023-06-22 Владимир Евгеньевич НЕБОЛЬСИН Pharmaceutical composition of 1-[2-(1-methylimidazole-4-yl)-ethyl]perhydroazine-2,6-dione for treating upper respiratory tract diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076620A3 (en) * 2005-01-14 2006-12-28 Cephalon Inc Bendamustine pharmaceutical compositions for lyophilisation
WO2010063476A2 (en) * 2008-12-03 2010-06-10 Astellas Deutschland Gmbh Solid dosage forms of bendamustine

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE159289C (en) * 1903-10-08 1905-03-16
US20040072889A1 (en) * 1997-04-21 2004-04-15 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
DE19826517B4 (en) * 1998-06-15 2006-03-23 Baxter Healthcare S.A. Process for the preparation of film-coated tablets with cyclophosphamide as active ingredient and cyclophosphamide film-coated tablet produced therefrom
US7374779B2 (en) 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US20030105141A1 (en) 2001-04-17 2003-06-05 Ping Gao Finely self-emulsifiable pharmaceutical composition
DE10304403A1 (en) * 2003-01-28 2004-08-05 Röhm GmbH & Co. KG Process for the preparation of an oral dosage form with immediate disintegration and drug release
JP2006518380A (en) 2003-01-31 2006-08-10 スミスクライン・ビーチャム・コーポレイション Solid dispersion composition
EP1605916A4 (en) * 2003-02-12 2012-02-22 R & P Korea Co Ltd Solvent system of hardly soluble drug with improved elution rate
CA2519408C (en) * 2003-04-04 2011-01-18 Genentech, Inc. High concentration antibody and protein formulations
AR054094A1 (en) * 2004-11-05 2007-06-06 Cephalon Inc CANCER TREATMENTS
US8105625B2 (en) * 2007-04-05 2012-01-31 University Of Kansas Rapidly dissolving pharmaceutical compositions comprising pullulan
MX2010000465A (en) 2007-07-12 2010-08-30 Tragara Pharmaceuticals Inc Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders.
US20100209927A1 (en) * 2007-11-06 2010-08-19 Menon Vinod P Processing device tablet
AR072777A1 (en) 2008-03-26 2010-09-22 Cephalon Inc SOLID FORMS OF BENDAMUSTINE CHLORHYDRATE
HUE039187T2 (en) * 2008-06-06 2018-12-28 Boehringer Ingelheim Int Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
US8349353B2 (en) 2008-06-27 2013-01-08 Otonomy, Inc. Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders
DK2367542T3 (en) * 2008-12-03 2014-03-10 Astellas Deutschland Gmbh ORAL DOSAGE FORMS OF BENDAMUSTIN
US20100273730A1 (en) * 2009-04-27 2010-10-28 Innopharmax, Inc. Self-emulsifying pharmaceutical compositions of hydrophilic drugs and preparation thereof
EP2424506A1 (en) * 2009-04-28 2012-03-07 Cephalon, Inc. Oral formulations of bendamustine
US20100297194A1 (en) 2009-04-30 2010-11-25 Nathaniel Catron Formulation for oral administration of apoptosis promoter

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076620A3 (en) * 2005-01-14 2006-12-28 Cephalon Inc Bendamustine pharmaceutical compositions for lyophilisation
WO2010063476A2 (en) * 2008-12-03 2010-06-10 Astellas Deutschland Gmbh Solid dosage forms of bendamustine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
solubilizing excipients in oral and injectable formulations;Strickley R G;《pharmaceutical research》;20040201;第21卷(第2期);209-213 *

Also Published As

Publication number Publication date
FI2575785T3 (en) 2023-01-31
US10485787B2 (en) 2019-11-26
US20130209558A1 (en) 2013-08-15
NZ603874A (en) 2014-08-29
TWI556819B (en) 2016-11-11
BR112012030658B1 (en) 2022-08-02
EA201291249A1 (en) 2014-07-30
EA027786B1 (en) 2017-09-29
TW201210591A (en) 2012-03-16
CL2012003340A1 (en) 2014-03-28
JP2013527206A (en) 2013-06-27
AU2011260614B2 (en) 2016-12-15
CO6640268A2 (en) 2013-03-22
KR20130116164A (en) 2013-10-23
CN103037852A (en) 2013-04-10
ES2935792T3 (en) 2023-03-10
ZA201208822B (en) 2014-08-27
PL2575785T3 (en) 2023-02-20
MX2012013873A (en) 2013-07-03
WO2011151086A1 (en) 2011-12-08
JO3659B1 (en) 2020-08-27
SG185794A1 (en) 2013-01-30
AR081575A1 (en) 2012-10-03
IL272501A (en) 2020-03-31
JP2016172763A (en) 2016-09-29
AU2011260614A1 (en) 2013-01-10
JP6259490B2 (en) 2018-01-10
DK2575785T3 (en) 2023-01-30
IL223309B (en) 2020-05-31
BR112012030658A2 (en) 2016-08-16
KR101830147B1 (en) 2018-02-20
EP2575785B1 (en) 2022-10-26
CA2800277A1 (en) 2011-12-08
MY173881A (en) 2020-02-26
IL223309A0 (en) 2013-02-03
EP2575785A1 (en) 2013-04-10
US20150258070A1 (en) 2015-09-17

Similar Documents

Publication Publication Date Title
CN103037852B (en) The peroral dosage form of bendamustine and therapeutical uses thereof
CN105363037B (en) The peroral dosage form of bendamustine
CN102292073B (en) The solid dosage forms of bendamustine
TW201000472A (en) New solid pharmaceutical formulations comprising BIBW 2992
JP2020063292A (en) Capsule and powder formulations containing lanthanum compounds
US8367106B2 (en) Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby
CN106176745A (en) Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use
EP2538924B1 (en) Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation
TW201636008A (en) Very rapidly disintegrating tablet, and method for producing same
US20180344648A1 (en) Clobazam tablet formulation and process for its preparation
JP4842960B2 (en) Method for producing a compressed solid dosage form well suited for use with low water-soluble drugs and compressed solid dosage form produced thereby
BR112020019425A2 (en) PHARMACEUTICAL COMPOSITION UNDERSTANDING META-ARSENITE AND MANUFACTURING METHOD
Laha et al. Advances in solid dosage forms
JP5508311B2 (en) Method for producing a compressed solid dosage form well suited for use with low water-soluble drugs and compressed solid dosage form produced thereby
EP4284361A1 (en) Novel formulation for treating copper metabolism-associated diseases or disorders
Javaheri Wet granulated liquisolid drug delivery systems with hydrophobic and hydrophilic drugs
CN115989023A (en) System and method for multiple drug delivery

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1179859

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1179859

Country of ref document: HK

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160615

CF01 Termination of patent right due to non-payment of annual fee